REVIEW Open Access
Novel targeted therapeutics: inhibitors of MDM2,
ALK and PARP
Yuan Yuan
1
, Yu-Min Liao
2
, Chung-Tsen Hsueh
1
and Hamid R Mirshahidi
1*
Abstract
We reviewed preclinical data and clinical development of MDM2 (murine double minute 2), ALK (anaplastic
lymphoma kinase) and PARP (poly [ADP-ribose] polymerase) inhibitors. MDM2 binds to p53, and promotes
degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule
inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor
tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC).
Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated
promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear
enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway.
Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves
clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor,
demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5
other PARP inhibitors currently under active clinical investigation.
Introduction
Modern cancer therapeutics has evolved from non-spe-
cific cytotoxic agents that affect both normal and cancer
cells to targeted therapies and personalized medicine.
Targeted therapies are directed at unique molecular sig-
nature of cancer cells to produce greater efficacy with
less toxicity. The development and use of such thera-
peutics allow us to practice personalized medicine and
improve cancer care. In this review, we summarized pre-
clinical data and clinical development of three important
targeted therapeutics: murine double minute 2 (MDM2),
anaplastic lymphoma kinase (ALK) and poly [ADP-
ribose] polymerase (PARP) inhibitors.
Murine Double Minute 2
MDM2, also known as HDM2 in human, is a negative
regulator of tumor suppressor p53 [1]. MDM2 encodes
a90-kDaproteinwithap53bindingdomainattheN-
terminus, and a RING (really interesting gene) domain
at the C-terminus functioning as an E3 ligase responsi-
ble for p53 ubiquitylation [2]. When wild-type p53 is
activated by various stimuli such as DNA damage,
MDM2 binds to p53 at the N-terminus to inhibit the
transcriptional activation of p53, and promote the
degradation of p53 via ubiquitin-proteasome pathway
[3,4]. MDM2 is overexpressed in a variety of human
cancers, including melanoma, non-small cell lung can-
cer (NSCLC), breast cancer, esophageal cancer, leuke-
mia, non-Hodgkin’s lymphoma and sarcoma [5].
MDM2 can interfere with p53-mediated apoptosis and
growth arrest of tumor, which is the major oncogenic
activity of MDM2 [6,7]. Additionally, MDM2 can
cause carcinogenesis independent of p53 pathway [8].
In tumor with homozygous mutant p53, loss of
MDM2, which mimics the inhibition of the MDM2-
p53 interaction, can cause stabilization of mutant p53
and increased incidence of metastasis [9]. Overexpres-
sion of MDM2 has been shown to correlate positively
with poor prognosis in sarcoma, glioma and acute lym-
phocytic leukemia [10]. In NSCLC, there have been
conflicting results as to whether MDM2 overexpres-
sion is associated with worse or better prognosis, but
the subset analysis has demonstrated a poor prognostic
factor for early-stage NSCLC patients, particularly
those with squamous cell histology [11].
* Correspondence: hmirshah@llu.edu
1
Division of Medical Oncology and Hematology, Loma Linda University
Medical Center, Loma Linda, CA 92354, USA
Full list of author information is available at the end of the article
Yuan et al.Journal of Hematology & Oncology 2011, 4:16
http://www.jhoonline.org/content/4/1/16 JOURNAL OF HEMATOLOGY
& ONCOLOGY
© 2011 Yuan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creative commons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, pro vided the original work is properly cited.
Preclinical development of MDM2 inhibitors
Inhibition of MDM2 can restore p53 activity in cancers
containing wild-type p53, leading to anti-tumor effects
with apoptosis and growth inhibition [12-14]. Animal
studies have shown reactivation of p53 function can
lead to the suppression of lymphoma, soft tissue sar-
coma, and hepatocellular carcinoma [15-17]. Ventura et
al. have designed a reactivatable p53 knockout animal
model by a a Cre-loxP-based strategy, which a transcrip-
tion-translation stop cassette flanked by loxP sites (LSL)
is inserted in the first intron of the endogenous wild-
type p53 locus leading to silencing of p53 expression.
Cells from homozygous p53LSL/LSL mice are function-
ally equivalent to p53 null (p53-/-) cells, and p53LSL/
LSL mice are prone to develop lymphoma and sarcoma.
Due to the presence of flanking loxP sites, the stop cas-
sette can be excised by the Cre recombinase, which
causes reactivation of p53 expression and regression of
autochthonous lymphomas and sarcomas in mice [16].
These results have provided an encouraging direction
for p53-target therapeutic strategy utilizing inhibition of
MDM2. Since the interaction and functional relationship
between MDM2 and p53 have been well characterized,
small-molecule inhibitors of MDM2 have been devel-
oped by high-throughput screening of chemical libraries
[18-20]. As shown in table 1, there are three main cate-
gories of MDM2 inhibitors: inhibitors of MDM2-p53
interaction by targeting to MDM2, inhibitor of MDM2-
p53 interaction by targetingtop53,andinhibitorsof
MDM2 E3 ubiquitin ligase. The binding sites and
mechanism of action for these inhibitors are further illu-
strated in Figure 1.
Nutlins, consisting of nutlin 1, 2 and 3, analogs of cis-
imidazoline, fit in the binding pocket of p53 in MDM2
and inhibit the interaction between MDM2 and p53
[21,22]. Nutlin-3, an analog of the series, has the most
potent binding capacity and lowest inhibition concentra-
tion, induced p53 levels, and activated p53 transcrip-
tional activity [23]. Nutlin-3 has been shown to exhibit a
broad activity against various cancer models with wild-
type p53, such as breast, colon, neuroblastoma, mantle
cell lymphoma and osteosarcoma [24-27]. Nutlin-3 acti-
vates p53 and induces apoptosis and cellular senescence
in myeloid and lymphoid leukemic cells {Hasegawa,
2009 #149}. In the absence of functional p53, nutlin-3
interrupts the interaction between p73 and MDM2, and
increases p73 transcriptional activity, leading to
enhanced apoptosis and growth inhibition of leukemic
cell [30].
Table 1 MDM2 inhibitors in development
Chemical series Therapeutics Development stage
Inhibitors of MDM2-p53 interaction by targeting to MDM2
Cis-imidazoline RO5045337 (RG7112; Nutlin-3) Phase I:
Advanced solid tumors and hematological malignancy
Benzodiazepinedione TDP521252 & TDP665759 Preclinical
Spiro-oxindoles MI-219,
MI-319 & other MI compounds
Preclinical
Isoquinolinone PXN727 & PXN822 Preclinical
Inhibitor of MDM2-p53 interaction by targeting to p53
Thiophene RITA
(NSC 652287)
Preclinical
E3 Ligase Inhibitors
5-Deazaflavin HLI98 compounds Preclinical
Tryptamine JNJ-26854165 Phase I:
Advanced solid tumors
RITA, reactivation of p53 and induction of tumor cell apoptosis.
Reference; [23,36,37,130-132,134-139].
Figure 1 Schematic representation of the MDM2 and p53
proteins, and the binding areas for small-molecule inhibitors.
Nutlin, cis-imidazoline; TDP, benzodiazepinedione; MI, spiro-
oxindoles; PXN, isoquinolinone; HLI98, 5-deazaflavin; JNJ-26854165,
tryptamine; RITA, thiophene; RING, really interesting new gene
(signature domain of E3 ligase). Binding of either HLI98 or JNJ-
26854165 to RING domain of MDM2 can block the interaction of
ubiquitinated MDM2-p53 protein complex to the proteasome.
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MDM4 (also known as MDMX), an MDM2 homolog,
binds p53 and inhibits p53 activity without causing
degradation of p53 degradation [31]. Furthermore,
despite the similarity between MDM2 and MDM4,
MDM2 inhibitors such as nutlin-3 are far less effective
against MDM4 [32]. Small-molecule inhibitor of MDM4
has been developed through a reporter-based drug
screening [33]. MDM4 inhibitor not only can activate
p53 and induce apoptosis in breast cancer MCF-7 cells,
but can also synergize with MDM2 inhibitor for p53
activation and induction of apoptosis.
Clinical development of MDM2 inhibitors
JNJ-26854165, a novel tryptamine derivative, is an oral
MDM2 inhibitor. Pre-clinical studies have shown bind-
ing of JNJ-26854165 to RING domain of MDM2 inhibits
the interaction of MDM2-p53 complex to the protea-
some, and increases p53 level [19]. Furthermore, induc-
tion of apoptosis and anti-proliferation independent of
p53 in various tumor models including breast cancer,
multiple myeloma and leukemia were shown [34-36].
The presence of p53-independent apoptotic activity in
addition to p53-mediated apoptosis is regarded as an
advantage to prevent the selection of p53 mutant sub-
clones in cancer during treatment of JNJ-26854165.
Results for phase I study (clinicaltrial.gov identifier:
NCT00676910) using continuously daily oral dosing in
patients with advanced solid tumors were presented in
2009 annual meeting of American Society of Clinical
Oncology (ASCO) [37]. Forty-seven patients were trea-
ted at 11 dose levels, ranging from 4 to 400 mg daily.
Treatment was well tolerated with frequent adverse
events in grade 1-2: nausea, vomiting, fatigue, anorexia,
insomnia, electrolyte imbalance, and mild renal/liver
function impairment. No hematological or cardiovascu-
lar toxicities were observed. One patient at 300 mg dose
level experienced dose-limiting toxicity (DLT) with
grade 3 asymptomatic QTc prolongation, which resolved
after discontinuation of treatment. Dose escalation was
stopped at 400 mg dose level due to 2 out of 3 patients
had DLT including one grade 3 skin rash and one grade
3 QTc prolongation. There was no objective response,
but 3 patients with prolonged SD including one breast
cancer overexpressing human epidermal growth factor
receptor 2. Pharmacokinetic study demonstrated linear
pharmacokinetics in 20 to 400 mg dose range, with pre-
clinical determined therapeutic concentration achieved
at dose level of 300 mg and above. Pharmacodynamic
study showed upregulation of p53 in skin, increase of
HDM2 levels in tumors, and increase of plasma macro-
phage inhibitory cytokine-1 (MIC-1) levels in dose-
dependent manner. MIC-1, a transforming growth fac-
tor-B superfamily cytokine, is induced by p53 activation,
and secreted MIC-1 levels can serve as a biomarker for
p53 activation [38]. Dose level of 350 mg was used on
expanded cohort of patients to confirm maximum toler-
ated dose, and trial with alternate dosing schedule to
minimize QTc prolongation was started with 150 mg
twice a day.
RO5045337 (RG7112), an oral formulation of nutlin-3,
is currently in phase I studies for patients with advanced
solid tumors (NCT00559533), and refractory acute leu-
kemias and chronic lymphocytic leukemia
(NCT00623870). Both studies are to determine the max-
imum tolerated dose and the optimal dosing schedule of
RO5045337, administered as monotherapy. Preliminary
data has shown acceptable safety profiles with responses
seen in patients with liposarcoma, acute myelogenous
leukemia and chronic lymphocytic leukemia.
Anaplastic Lymphoma Kinase
ALK is a 1620 amino acid transmembrane protein, con-
sisting of extracellular domain with amino-terminal sig-
nal peptide, intracellular domain with a
juxtamembranous segment harboring a binding site for
insulin receptor substrate-1, and a carboxy-terminal
kinase domain [39]. ALK is a member of the insulin
receptor tyrosine kinases, and the physiological function
of ALK remains unclear [40]. Translocation of ALK
occurs in about 50% of anaplastic large-cell lymphoma
(ALCL), and 80% of them have the t (2; 5) chromosomal
translocation with NPM-ALK expression [41]. The t (2;
5) translocation generates a fusion protein with carboxy-
terminal kinase domain of ALK on chromosome 2, and
the amino-terminal portion of nucleophosmin (NPM)
on chromosome 5. NPM is the most common fusion
partner of ALK, but at least six other fusion partners
have been identified. In these fusion proteins, the
amino-terminal portion is responsible for protein oligo-
merization, which activates ALK kinase and downstream
signaling such as Akt, STAT3, and extracellular signal-
regulated kinase 1 and 2 [42] (Figure 2).
Mutations of ALK have been identified in 6-12% of
sporadic neuroblastoma, and preclinical studies have
demonstrated these mutations promote ALK kinase
activity leading to oncogenic events [43]. It has been
postulated that activation of ALK provides oncogenic
addiction to tumors harboring activating mutation or
translocation of ALK [44]. Knock-down of ALK by
small hairpin RNA targeting ALK in NPM-ALK-con-
taining tumor models gives raise to growth inhibition
and apoptosis [45]. This indicates inhibition of ALK
may be an effective therapeutic strategy for tumors har-
boring ALK activation.
Echinoderm microtubule-associated protein-like 4
(EML4) is a 120 KDa cytoplasmic protein, which
involves in the formation of microtubules and microtu-
bule binding protein [46]. EML4-ALK is a novel fusion
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gene arising from an inversion on the short arm of
chromosome 2 [Inv (2)(p21p23)] that joined exons 1-13
of EML4 to exons 20-29 of ALK [47,48]. Soda et al.
identified this fusion gene as a transforming activity in
mouse 3T3 fibroblasts from DNA of lung cancer in a
Japanese man with a smoking history in 2007 [48].
EML4-ALK fusion protein consists of the complete tyro-
sine kinase domain of ALK at and the carboxy-terminal,
and promoter of the 5’partner gene controls the tran-
scription of the resulting fusion gene. Multiple variants
of EML4-ALK have been identified, and all the variants
encode the same cytoplasmic portion of ALK but differ-
ent truncations of EML4 (at exons 2, 6, 13, 14, 15, 18,
and 20). In lung cancer the chimeric protein involves
ALK fused most commonly but not exclusively to
EML4. Other rare fusion partners are TRK-fused gene
11 (TFG 11) and KIF5B (Kinesin heavy chain) [47-51].
ALK gene rearrangements and the resulting fusion pro-
teins in tumor specimen can be identified by fluorescent
in situ hybridization (FISH), immunohistochemistry
(IHC), and reverse transcription-polymerase chain reac-
tion (RT-PCR).
The presence of EML4-ALK fusion is identified in
approximately 3-13% of NSCLC, and mutually exclusive
with the presence of epidermal growth factor receptor
(EGFR) mutation [48,52-55]. EML4-ALK fusion
Figure 2 Schematic representation of the EML-4 and ALK translocation. A) Fusion of the N-terminal portion of EML4 (comprising the basic
region, the HELP domain and part of the WD-repeat region) to the intracellular region of ALK (including the tyrosine kinase domain). TM,
transmembrane domain. B) Both the ALK gene and the EML4 gene plot to chromosome 2p, but have opposite orientations. In the NSCLC EML4
is interrupted at a position 3.6 kb downstream of exon 13 and is attached to a position 297 bp upstream of exon 21 of ALK, creating the EML4-
ALK (variant 1) fusion gene.
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transcript is not identified in other cancer types such as
gastrointestinal and breast cancers [56]. Shaw et al.
investigated the clinical features of NSCLC patients har-
boring EML4-ALK fusion rearrangement [55]. Among
141 patients, they found 19 (13%) patients carried the
EML4-ALK rearrangement, 31 (22%) harbored an acti-
vating EGFR mutation, and 91 (65%) were wild type for
both ALK and EGFR (designated WT/WT). EML4-
ALK-positive patients were significantly younger than
patients with either EGFR mutation or WT/WT (P <
0.001 and P = 0.005, respectively). EML4-ALK-positive
patients were more likely to be men than patients with
either EGFR mutation or WT/WT (P = 0.036 and P =
0.039, respectively). EML4-ALK-positive patients were
significantly never or light smokers compared with the
WT/WT patients (P < 0.001), and did not benefit from
treatment with EGFR tyrosine kinase inhibitors (TKIs).
Eighteen EML4-ALK-positive patients had adenocarci-
noma and one patient had mixed adenosquamous his-
tology.However,patientswithEML4-ALK-positive
NSCLC did not have exclusively adenocarcinoma histol-
ogy in two other studies [51,53].
Focusing on the clinical outcome, Shaw et al. exam-
ined 477 NSCLC patients, and identified 43 patients
(9%) with EML4-ALK rearrangements, 99 patients (21%)
with EGFR mutations, and 335 patients (70%) with WT/
WT [57]. EML4-ALK-positive patients were significantly
younger (median age 54 vs 64 years old, p < 0.001) and
more likely to be never or light smokers (90% vs 37%, p
< 0.001), compared with WT/WT patients. There was
no difference in overall survival (OS) between patients
with EML4-ALK fusion and EGFR mutation (1-year OS:
82% vs 81%, p = 0.79); however, both groups demon-
strated a longer OS than WT/WT patients (1-year OS
66%, p < 0.001). This data suggests the better outcome
in patients with EML4-ALK rearrangement vs. patients
with WT/WT may be related to differences in biology,
demographic features, and availability of targeted
therapies.
Preclinical development of ALK inhibitors
The development of ALK small-molecule inhibitors has
been hampered due to lack of ALK protein structure.
Initial testing and development of ALK inhibitors were
done with naturally occurring sources such as stauros-
porine and HSP90 inhibitors, which are not potent and
specific inhibitors of ALK [58]. Subsequently, using
homology modeling to assist the screening and synth-
esis, more potent and specific ALK inhibitors have been
developed [59]. Although there are multiple partners for
the ALK translocation, all the fusion proteins contain
the ALK kinase domain and should be susceptible to
ALK kinase inhibition. As shown in table 2, there are at
least 9 different chemical classes of small-molecule inhi-
bitors of ALK being developed.
PF-2341066 (Crizotinib), derivative of aminopyridine,
was initially developed as a potent, orally bioavailable,
ATP-competitive small-molecule inhibitor of c-MET
and hepatocyte growth factor receptor [60]. Further
investigation has indicated Crizotinib is a potent inhibi-
tor of ALK as well, and half maximal inhibitory concen-
tration (IC
50
) for either c-MET or ALK overexpressing
cell line is ~20 nM. Crizotinib suppresses the prolifera-
tion of ALCL cell line with ALK activation, but not in
ALCL cell lines without ALK activation. Crizotinib inhi-
bits phosphorylation of ALK, and causes complete
regression of ALCL harboring NPM-ALK fusion in
xenograft model [61]. Crizotinib also inhibits the prolif-
eration in NSCLC (such as H3122) and neuroblastoma
cell lines harboring ALK activation [62]. Experiments
Table 2 ALK inhibitors in development
Chemical series Therapeutics Development stage
Aminopyridine PF-2341066 (crizotinib) Phase II/III: NSCLC; phase I/II: advanced solid tumors, neuroblastoma, and ALCL
Diaminopyrimidine CEP-28122 Preclinical
IND application expected
Structure undisclosed AP-26113 Preclinical
IND application expected in 2011
Structure undisclosed X-276 Preclinical
Pyridoisoquinoline F91873 and F91874 Preclinical
Pyrrolopyrazole PHA-E429 Preclinical
Indolocarbazole CEP-14083 and CEP-14513 Preclinical
No further development
Pyrrolopyrimidine GSK1838705A Preclinical
No further development
Dianilinopyrimidine NVP-TAE684 Preclinical
No further development
NSCLC, non-small cell lung cancer; ALCL, anaplastic large cell lymphoma
Reference [60,61,64,65,140-150]
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using NCI-H441 NSCLC xenografts showed a 43%
decrease in mean tumor volume, with 3 of 11 mice
exhibiting a >30% decrease in tumor mass and 3 animals
with no evidence of tumor at the end of the 38-day cri-
zotinib treatment [60]. Crizotinib is currently under-
going active clinical investigation in NSCLC.
Additionally, phase I/II study is conducted in patients
with advanced malignancy such as ALCL or neuroblas-
toma (NCT00939770).
Second-generation ALK inhibitors such as AP-26113
and X-276 are considered more potent and selective
inhibitors of ALK than crizotinib. AP-26113, an orally
bioavailable inhibitor of ALK with undisclosed structure,
is developed by Ariad [63]. During preclinical investiga-
tion, AP-26113 has been shown to inhibit not only the
wild-type ALK but also mutant forms of ALK, which
are resistant to the first-generation ALK inhibitor such
as crizotinib. Further studies have demonstrated AP-
26113 is at least 10-fold more potent and selective in
ALK inhibition than crizotinib [64,65].
Clinical development of ALK inhibitors
In 2009 annual meeting of ASCO, Kwat et al. reported
the results of phase I dose escalation study and
expanded phase II study of crizotinib [66]. Thirty-seven
patients with advanced solid tumors including 3 NSCLC
patients were enrolled in phase I study. The maximum
tolerated dose of crizotinib was 250 mg orally twice a
day,and2fatigueDLTwerenotedinthenextdose
level at 300 mg twice a day. The major side effects were
fatigue, nausea, vomiting and diarrhea; but were man-
ageable and reversible. There was 1 partial response
(PR) in a sarcoma patient with ALK rearrangement.
Additionally, a dramatic clinical response was observed
in a NSCLC patient harboring EML4-ALK rearrange-
ment. Therefore, an expanded phase II study using 250
mg of crizotinib twice a day was conducted in 27
NSCLC patients harboring EML4-ALK tumor deter-
mined by FISH. In the first 19 evaluable patients, there
were 17 patients with adenocarcinoma (90%) and 14
non-smokers (74%). Overall response rate (RR) was 53%,
and disease control rate (DCR; complete response [CR]/
PR/stable disease [SD]) was 79% at 8 weeks. Only 4
patients (21%) progressed after 8 weeks of treatment,
despite more than 60% of patients received 2 or more
lines of treatment prior to entering this study.
Bang et al. presented the follow up results on the
expanded phase II study of crizotinib in NSCLC patients
with EML4-ALK rearrangement in 2010 annual meeting
of ASCO [67]. Eighty-two patients were evaluable, with
96% adenocarcinoma, 76% never-smokers and ~95%
having prior treatment. Overall RR was 57%, with esti-
mated 6-month progression-free survival (PFS) rate of
72%, and DCR of 87% at 8 weeks. The median
progression-free survival was not yet mature, and the
median duration of treatment was 25.5 weeks. Radiolo-
gical responses typically were observed at the first or
second restaging CT scan. Main side effects were nau-
sea, diarrhea and visual disturbance on light/dark
accommodation without abnormality on eye examina-
tion. The results of this phase II study have been
recently published [68].
Based on these encouraging results, a randomized
phase III trial comparing crizotinib to standard second-
line cytotoxic chemotherapy docetaxel and pemetrexed
in patients with ALK-positive NSCLC has now com-
menced (NCT00932893). The combination of erlotinib
and crizotinib is also being tested in patients who failed
prior chemotherapies regardless of EML4/ALK translo-
cation status (NCT00965731). A phase III study to eval-
uate crizotinib as first line therapy in EML4-ALK
translocation patients compare to standard platinum
based chemotherapy is underway (NCT01154140).
Poly ADP-Ribose Polymerases
PARPs are a family of nuclear enzymes that regulates
the repair of DNA single-strand breaks (SSBs) through
the base-excision repair (BER) pathway [69]. Upon DNA
damage, PARP cleaves nicotinamide adenine dinucleo-
tide (NAD
+
) to generate poly (ADP-ribose) (PAR) poly-
mers, which are added onto DNA, histones, DNA repair
proteins and PARP [70,71]. These hetero- and auto-
modification processes mediated by PARP lead to
recruitment of repair machinery to facilitate BER pro-
cess. Among the 17 members of PARP, PARP-1 and
PARP-2 are the only members known to be activated by
DNA damage and may compensate for each other [72].
PARP-1 is best characterized and responsible for most if
not all the DNA-damage-dependent PAR synthesis;
exhibits with N-terminal DNA-binding domain, central
auto-modification domain, and C-terminal catalytic
domain, which is the “signature”for PARP family.
Although lacks of central auto-modification domain,
PARP-2 shares ~70% homology of catalytic domain as
PARP-1, and provides residual PARP activity (~15%) in
the absence of PARP-1 [73]. The physiological functions
of PARP-1 and PARP-2 have been further explored in
knockout models [74]. Double PARP-1 and PARP-2
knockout mice are lethal at the embryonic stage. Knock-
out of either PARP-1 or PARP-2 results in increased
genomic instability by accumulation of DNA SSBs, and
causes hypersensitivity to ionizing radiation and alkylat-
ing agents. Additionally, PARP-1 also plays important
roles in cellular responses to ischemia, inflammation
and necrosis.
Targeting the PARP-mediated DNA repair pathway is
a promising therapeutic approach for potentiating the
effects of chemotherapy and radiation therapy and
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overcoming drug resistance [75]. However, the most
exciting use of PARP inhibitors may be utilizing a phe-
nomenon called synthetic lethality [76]. Synthetic lethal-
ity is a cellular condition in which simultaneous loss of
two nonessential mutations results in cell death, which
dose not occur if either gene products is present and
functional [77]. Tumors with DNA repair defects, such
as those arising from patients with BRCA mutations
were found to be more sensitive to PARP inhibition due
to synthetic lethality. The BRCA1 and BRCA2 gene
encodes large proteins that coordinate the homologous
recombination repair double strand breaks (DSBs) path-
way [78]. Since BRCA1/2-mutated tumors cannot utilize
homologous recombination to repair DSBs, exposing
these cells to PARP inhibitor, which shuts down BER
rescue pathway, will lead to accumulation of DNA
damage, genomic instability and cell death (Figure 3).
Preclinical development of PARP inhibitors
Inhibition of PARP has been developed in the laboratory
for more than 30 years, with analogues mimicking nicoti-
namide component of NAD
+
for binding to catalytic site
of PARP [70,79]. Preclinical data reporting efficacy of
PARP inhibitors in a BRCA mutated population was initi-
ally reported in 2005 [80,81]. Bryant et al. revealed that
low concentrations of PARP inhibitors produced cyto-
toxicity on BRCA2-deficient cell lines with defects in
homologous recombination, but not in cell lines with
intact homologous recombination. When BRCA2 func-
tion was restored in these cell lines, the cells were no
longer subject to inhibition of PARP. In other breast can-
cer cell lines such as MCF-7 and MDA-MB-231, similar
sensitivity to PARP inhibition was observed when
BRCA2 was depleted. Similarly, Farmer et al. demon-
strated that PARP inhibitors NU1025 and AG14361 were
highly cytotoxic in BRCA2-deficient VC-8 cells [80].
Additionally, cell death increased when BRCA1/2 defi-
cient cells were transfected with small interfering RNA
targeting PARP-1. Enhanced sensitivity to PARP inhibi-
tion in BRCA-deficient cells was observed when DNA-
damaging agents were added in vitro. These preclinical
data serve as proof-of-concept for synthetic lethality in
BRCA-deficient cell lines and provide important rationale
for studying PARP inhibitors in patients with BRCA1/2-
asssociated breast and ovarian cancer.
Further investigations have identified triple-negative
breast cancer (TNBC, breast cancer without over-expres-
sion of estrogen, progesterone and HER2-neu receptors,
accounts for about 15 percent of all breast cancers) and
sporadic serous ovarian cancer without mutations of
BRCA1/2 but exhibit properties of BRCA1- or BRCA2-
deficient cells, known as “BRCAness”[82]. BRCAness
cancers have defects in homologous recombination due
to dysfunctional BRCA1/2 from epigenetic modification,
and/or deficiency in proteins involved in homologous
recombination repair pathways, such as RAD51, RAD54,
DSS1, RPA1, ATM, CHK2 and PTEN [83-85]. Preclinical
studies have shown BRCAness cancer cells are more sen-
sitive to PARP inhibition especially in the presence of
DNA-damaging agents such as cisplatin, vs. non-BRCA-
ness [86]. These important findings have further
expanded the therapeutic application of PARP inhibitors
in cancers with acquired defect in homologous recombi-
nation other than germline BRCA mutations.
As shown in table 3, there are currently 9 different
PARP inhibitors at different stages of clinical development,
and at least 3 highly selective PARP inhibitors in preclini-
cal development. Because both PARP-1 and PARP-2 share
high degree of homology in catalytic domain, most of the
PARP inhibitors under clinical development do not have
significant differential activity against either PARP-1 or
PARP-2 [69]. Using x-ray crystal structure and homology
Figure 3 Schematic representation of PARP and BRCA
mediated DNA repair in cells without exposure to PARP
inhibitor and BRCA mutation (A), and synthetic lethality in cells
with BRCA mutation exposing to PARP inhibitor (B).
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modeling, highly selective inhibitors against either PARP-1
or PARP-2 have been successfully developed [87-89].
Over-activation of PARP-1 due to DNA damage from
ischemic event is responsible for post-ischemic cell death
in neurons and myocardial cells, and PARP-1 knockout
mice are more resistant to the damage from ischemic
insults [90,91]. PARP inhibitors such as INO-1001 and
MP-124 have been studied in animal models and clinical
settings as neuroprotectant and cardiac protectant during
ischemic insults [92-94].
PARP-5a and PARP-5b, also known as tankyrase 1
and tankyrase 2, are involved in telomere metabolism
and Wnt/b-catenin signaling [69]. Moreover, tankyrase
inhibition imposes selective lethality on BRCA deficient
cell lines [95]. XAV939, a small molecule which sup-
presses b-catenin-mediated transcription by stabiling
axin and degrading b-catenin, is found to inhibit tan-
kyrases [96]. Molecule like XAV939 can be used to tar-
get cancers harboring BRCA (such as breast cancer)
and/or dysregulated Wnt-b-catenin signaling (such as
colorectal cancer) without affecting PARP-1.
Clinical development of PARP inhibitors
Seven PARP inhibitors are currently in clinical devel-
opment in oncology. Most of phase I studies have used
pharmacodynamic analysis of PARP-1 activity in per-
ipheral blood mononuclear cells (PBMCs) to determine
the optimal PARP inhibitory dose. There are 2 main
investigational approaches: single-agent study in
BRCA-associated and BRCAness cancers; combination
study with DNA-damage agent and/or radiation. BSI-
201 (Sanofi-Aventis) is currently in a phase III trial for
TNBC in combination with gemcitabine and carbopla-
tin. AZD2281 (Astra-Zeneca), AG-014966 (Pfizer) and
ABT-888 (Abott), are in phase II clinical trials as sin-
gle agent or in combination with chemotherapy. MK-
4827 (Merck), CEP-9722 (Cephalon) and E7016 (Eisai)
are in phase I clinical trials. INO-1001 (Inotek) is no
longer in clinical development after completion of a
phase IB study in combination with temozolomide in
patients with advanced melanoma [97], and there is no
updated information available on this compound
[98,99].
Table 3 PARP inhibitors in development
Chemical
series
Therapeutics Development stage
Benzamide BSI-201
(iniparib)
Phase III
Gemcitabine and carboplatin ± BSI-201 in breast and lung cancers; phase I/II: single agent or combination with
chemotherapy in various cancer types including glioma and ovarian cancer
Phthalazinone AZD2281
(olaparib)
Phase I/II
Single agent or combination with chemotherapy in various cancer types including breast, ovarian and colorectal
cancers
Tricyclic indole AG-014699
(PF-01367338)
Phase II
Single agent in BRCA-associated breast or ovarian cancer; Phase I: combination with chemotherapy in advanced
solid tumors
Benzimidazole ABT-888
(Veliparib)
Phase II
Combination with chemotherapy in various cancer types including breast cancer, colorectal cancer, glioblastoma
multiforme and melanoma; phase I: combination with radiation
Indazole MK-4827 Phase I
Single agent; combination with carboplatin-containing regimens
Pyrrolocarbazole CEP-9722 Phase I
Combination with temozolomide in advanced solid tumors
Phthalazinone E7016
(GPI-21016)
Phase I
Combination with temozolomide in advanced solid tumors
Isoindolinone INO-1001 Phase I
Combination with temozolomide in melanoma (completed) without further investigation in oncology; phase II in
cardiovascular disease
Structure
undisclosed
MP-124 Phase I in acute ischemic stroke
Structure
undisclosed
LT-00673 Preclinical
Structure
undisclosed
NMS-P118 Preclinical
Structure
undisclosed
XAV939 Preclinical, highly selective against PARP-5 (tankyrase)
Reference; [94,96,97,100,101,103,106,108,115-117,119,122-125,151-156]
Yuan et al.Journal of Hematology & Oncology 2011, 4:16
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BSI-201 (Iniparib)
BSI-201 is different from other PARP inhibitors, due to
drug discovery from interacting with DNA binding
domain of PARP-1 instead of catalytic site of PARP
[100]. By disrupting the binding between PARP-1 and
DNA, BSI-201, a noncompetitive PARP-1 inhibitor,
attenuates PARP-1 activation. Phase I study of BSI-201 in
advanced solid tumors has demonstrated good tolerabil-
ity without an identified MTD with dose levels ranging
from 0.5 mg/kg to 8.0 mg/kg IV twice weekly. The most
common adverse event was gastrointestinal toxicity
(39%). At dose level of 2.8 mg/kg, PARP was inhibited in
PBMCsbygreaterthan50%afterasingledose,with
greater inhibition observed (80% or more) after multiple
dosing [101]. A phase IB study combining BSI-201 with
various chemotherapeutic agents such topotecan, gemci-
tabine, temozolomide, and carboplatin/paclitaxel in
patients with advanced solid tumors has shown accepta-
ble safety profiles at doses levels ranging from 1.1 to 8.0
mg/kg iv twice a week [102]. Significant PARP inhibition
was again noted at dose levels of 2.8 mg/kg or higher. Of
55 patients in this study, there were one CR (ovarian can-
cer), 5 PR (2 breast cancer, and 3 other cancer types) and
19 SD. In 2009, O’Shaughnessy et al. presented the
results of a randomized phase II study comparing gemci-
tabine plus carboplatin with or without BSI-201 (5.6 mg/
kg; iv; biweekly n days 1, 4, 8, and 11 every 21 days) in
patients with TNBC [103]. The addition of BSI-201
improved RR from 16% to 48% (p = 0.002), and DCR
from 21% to 62%. Median PFS was improved from 3.3 to
6.9 months (hazard ratio [HR] 0.34, p < 0.001). Final
result of this phase II study was reported at 2009 San
Antonio Breast Cancer Symposium with overall survival
was improved from 7.7 to 12.2 month (HR 0.5, p = 0.005)
[104]. It’s noted that no significant difference in myelo-
toxicity was seen between the two treatment arms. An
updated analysis reported at 2010 European Society for
Medical Oncology meeting showed PFS was improved
from 3.6 months to 5.9 months (HR 0.59) and DCR was
improved from 33.9% to 55.7% (p = 0.015), median over-
all survival benefit remain similar (7.7 months vs. 12.3
months, HR 0.57). A randomized phase III study compar-
ing gemcitabine plus carboplatin with or without BSI-201
in patients with TNBC is currently underway
(NCT00938652). Similar treatment design is used for an
ongoing phase III study in patients with stage IV squa-
mous cell lung cancer (NCT01082549). BSI-201 is also
currently being evaluated as single agent or combination
with chemotherapy in phase I/II studies in various cancer
types including glioma and ovarian cancer.
AZD2281 (Olaparib)
Fong et al. reported the results of phase I study of ola-
parib, which is an oral small-molecule PARP inhibitor
[105,106]. The frequently occurred toxicities were nau-
sea, vomiting, diarrhea, and fatigue. Maximum tolerated
dose (MTD) was identified at 400 mg twice daily, with
grade 3 fatigue and mood alteration DLT noted in one
of eight patients at this dose level. Grade 4 thrombocy-
topenia and grade 3 somnolence occurred in two of five
patients receiving 600 mg twice daily. In a group of 19
patients with breast, ovarian or prostate caners with
known BRCA mutation, RR of 47% and DCR of 63%
were observed without profound difference in toxicity
profiles in comparison with non-BRCA mutated patients
[106]. The subsequent phase II study in 27 breast cancer
patients with BRCA mutation (18 BRCA1 deficient and
9 BRCA2 deficient) showed RR of 41% and median PFS
of 5.7 months [107]. The pooled analysis of 50 ovarian
cancer patients with BRCA1/2-mutation treated on
phase I and II studies (11 on phase I, and 39 on phase
phase II receiving olaparib 200 mg twice daily) showed
RR of 40% and DCR of 46%, predominately in platinum-
sensitive group [108].
Two subsequent Phase II studies evaluating olaparib
in previously treated BRCA1/2-mutated breast cancer
and ovarian cancer patients were recently reported
[104,109,110]. In both studies, patients were treated
with either 100 mg or 400 mg of olaparib twice daily.
Fifty-seven ovarian cancer patients and 54 breast cancer
patients were studies respectively. Overall RR in the
ovarian cancer study was 33% in the high-dose group
and 13% in the low-dose group. Overall RR in the breast
cancer study was 41% in the high-dose group and 22%
in the low-dose group.
Interestingly, reported in 2010 annual meeting of
ASCO, a provocative phase II study of olaparib showed
promising results for women with high-grade serous
ovarian cancer regardless of BRCA mutation status
[111]. Patients with advanced breast or ovarian cancer
were treated with single agent olaparib 400 mg twice
daily continuously for 28-day cycle. Of 64 women with
ovarian cancer in the study, the overall RR was 41.2%
and 23.9%, respectively, for patients with and without
BRCA mutations. However, no response was seen in the
24 patients with TNBC treated with olaparib. This is the
first single-agent trial demonstrating promising activity
of olaparib in high-grade non-BRCA mutated sporadic
serous ovarian caner. The mechanism could be attribu-
ted by underlying DNA repair abnormalities, which may
lead to “BRCAness”[82,112].
Combinations of olaparib and chemotherapy agents
have been explored. Myelosuppresion decreases toler-
ability when combine olaparib with chemotherapy
agents [113]. Dent et al. reported a phase I/II study of
olaparib in combination with weekly paclitaxel as first
or second-line treatment in patients with metastatic
TNBC [114]. Olaparib 200 mg twice daily was given
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continuously with paclitaxel 90 mg/m
2
weekly for 3 of 4
weeks. Toxicity included 58% neutropenia, 63% diarrhea,
58% nausea, and 53% fatigue, and most were grade 1-2
except neutropenia. Of 19 patients treated in two
cohorts, RR of 33 to 40% and median PFS of 5.2 to 6.3
months were observed.
AG-014699 (PF-01367338)
AG-014699, an intravenous PARP inhibitor, was stu-
died in combination with temozolomide in advanced
solid tumors [115]. PARP inhibitory dose was decided
at 12 mg/m
2
IV daily for 5 days every 4 weeks based
on 74% to 97% inhibition of peripheral blood lympho-
cyte PARP activity. Mean tumor PARP inhibition at 5
h was 92% (range, 46-97%). No significant toxicity was
seen from AG-014699 alone, and AG-014699 showed
linear pharmacokinetics without interaction with
temozolomide. A phase II study with this combination
as 1
st
line treatment of 40 patients with metastatic
melanoma showed RR of 10% and SD of 10%, with
significant bone marrow suppression being the major
toxicity [116]. Currently, this compound is in phase II
study as single agent in patients with advanced
BRCA1/2 mutated breast or ovarian cancer
(NCT00664781), and in phase I study in combination
with cytotoxic agents in patients with advanced solid
tumor (NCT01009190).
ABT-888 (Veliparib)
ABT-888 is an oral PARP inhibitor. Preclinical studies
in breast cancer, melanoma and glioma models demon-
strated that ABT-888 potentates the chemotherapy
effect of a number of agents including temozolomide,
platinum, and irinotecan, as well as radiation [117]. Tan
et al. reported the preliminary result of a phase I trial of
ABT-888 in combination with cyclophosphamide in
patients with advanced solid tumors [118]. ABT-888 50
mg twice daily can be safely combined with cyclopho-
sphamide 750 mg/m
2
. ABT-888 does not alter the phar-
macokinetics of cyclophosphamide. This study is still
ongoing to determine the MTD of ABT-888 and cyclo-
phosphamide combination.
A phase I study of ABT-888 in combination with
metronomic cyclophosphamide revealed activity in
BRCA mutated ovarian cancer and TNBC [119]. A
phase II trial of ABT-888 40 mg twice daily on days 1
to 7 in combination with temozolomide 150 mg/m
2
,
days 1-5 on a 28 days cycles for metastatic breast cancer
was well tolerated [120]. However, activity was limited
to BRCA mutation carriers. Of 8 patients with BRCA1/2
mutation, 37.5% RR and 62.5% DCR were observed.
Medial PFS was 5.5 months in BRCA mutation carriers
vs. 1.8 months in non-carriers. This study calls into
question of “BRCAness”for at least this PARP inhibitor.
ABT-888 is currently being evaluated in many phase I/II
studies in combination with chemotherapy or radiation
in patients with advanced solid tumors.
MK-4827
MK-4827 is an orally bioavailable PARP inhibitor. This
compound displays potent PARP-1 and PARP-2 inhibi-
tion, and inhibits proliferation of breast cancer cells
with mutant BRCA-1 and BRCA-2 with IC
50
in the
range of 10-100 nM [121]. Sandhu et al reported phase
I result of MK-4827 in 59 patients with advanced solid
tumors in 2010 annual meeting of ASCO [122]. MTD
was identified at 300 mg daily with common toxicities
in nausea/vomiting, fatigue and thrombocytopenia. Two
out of six patients on 400 mg daily experienced DLT
with grade 4 thrombocytopenia was seen in 2 out of 6
patients received 400 mg daily. Antitumor activity was
observed in patients with BRCA-deficient cancers (32%
PR in 19 patients with ovarian cancer, and 50% PR in 4
patients with breast cancer). Additionally, PR was seen
in 1 patient with sporadic platinum-sensitive ovarian
cancer. These findings have shown good tolerability and
promising antitumor activity of MK-4827 in both
BRCA-deficient and sporadic cancers. Phase I study in
expanded cohorts with sporadic ovarian and prostate
cancers is currently underway (NCT00749502). Phase IB
dose escalation study of MK-4827 in combination with
carboplatin, carboplatin/paclitaxel or carboplatin/doxil
in patients with advanced solid tumors has also been
activated (NCT01110603).
CEP-9722
Preclinical studies have shown CEP-9722 enhances cel-
lular sensitivity toward temozolomide, irinotecan and
radiation in various cancer types such as glioblastoma,
colon cancer, neuroblastoma, and rhabdomyosarcoma
[123]. CEP-9722 is currently undergoing phase I trial as
single agent and in combination with temozolomide in
advanced solid tumor (NCT00920595).
E7016
E7016 (previously known as GPI-21016) is an orally
bioavailable PARP inhibitor. In murine leukemia
model, E7016 enhances cisplatin-induced cytotoxicity
and ameliorated cisplatin-induced neuropathy at the
same time, suggesting a role to improve the therapeu-
tic margin of certain cytotoxic agent [124]. Further
study in human glioblastoma cell line and xenograft,
E7016 enhances tumor radiosensitivity, and synergizes
with combination treatment of temozolomide and
radiation [125]. There is an ongoing phase I study with
dose escalation of E7016 in combination with temozo-
lomide in patients with advanced solid tumors and
gliomas (NCT01127178).
Yuan et al.Journal of Hematology & Oncology 2011, 4:16
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Summary
We reviewed preclinical data and clinical development
of MDM2, ALK and PARP inhibitors. Cancer treatment
is entering an exciting chapter in targeted therapies and
personalized medicine due to the advance of molecular
biology and medicinal chemistry. Most likely several
compounds from this review will be approved for clini-
cal use in the years to come. Many questions remain to
be answered: (1) what are the long-term safety and toxi-
cities of these inhibitors (2) how to use biomarkers to
selectpatientswhowillbenefitmostfromtheseinhibi-
tors (3) how to combine these targeted therapies with
cytotoxic agents or other treatment modality such as
radiation modality in selected patient population?
More than 50 percent of human tumors contain a
mutation or deletion of the p53 gene. Mutation of p53
can confer dominant-negative or gain-of-function effects
[126]. Dominant-negative effects lead to suppression of
wild-type p53 protein in heterozygous mutant cells and
a p53 null phenotype; gain-of-function effects result in
promotion of tumor development. There have been con-
cerns on the exposure of MDM2 inhibitors to tumors
with mutant p53, which potentially can have deleterious
effects due to stabilization of mutant p53 [127].
Cautions need to be taken with long-term use of
PARP inhibitors. PARP-1 serves important roles in
other cellular function such as transcription regulation,
initiation of a unique cell death pathway, restarting
stalled replication forks, and modulation of cellular
responses to ischemia, inflammation and necrosis [128].
Previous studies indicated that genetic ablation of
PARP-1 in combination with p53 knockout increased
cancer incidence in mice [129]. This raises concern that
long-term PAPR-1 inhibition could potentially increase
the risk of secondary malignancies.
Author details
1
Division of Medical Oncology and Hematology, Loma Linda University
Medical Center, Loma Linda, CA 92354, USA.
2
Department of Internal
Medicine, China Medical University Hospital, Taichung, Taiwan, China.
Authors’contributions
HRM and CTH designed the paper. YY, YML, CTH and HRM wrote the paper.
All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 27 January 2011 Accepted: 20 April 2011
Published: 20 April 2011
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doi:10.1186/1756-8722-4-16
Cite this article as: Yuan et al.: Novel targeted therapeutics: inhibitors of
MDM2, ALK and PARP. Journal of Hematology & Oncology 2011 4:16.
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