p53 Activation by small molecules: Application in oncology

Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 08/2005; 48(14):4491-9. DOI: 10.1021/jm058174k
Source: PubMed

ABSTRACT For Abstract see ChemInform Abstract in Full Text.

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    ABSTRACT: Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four diastereoisomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with Ki = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice.
    Journal of Medicinal Chemistry 12/2014; 57(24). DOI:10.1021/jm501541j · 5.48 Impact Factor
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    ABSTRACT: P53 is an important transcriptional factor that plays a pivotal role in different biological process (cell cycle, apoptosis, DNA repair, angiogenesis and cellular metabolism). While p53 binds to the promoter and increases the gene expression of Mdm2, MDM2 protein directly binds to p53 and inhibits its activity. Therefore, inhibitor of p53 and MDM2 has been considered as potential cancer therapeutic agent due to the critical inhibitory role of MDM2 on p53. Small-molecule inhibitor of p53-MDM2 has been designed to serve as an effective way to treat cancer. Several compounds have moved into different phase of clinical trials based on major advances in the development of small-molecule inhibitors in recent years. Since there are few reviews covering the structure-activity relationship analysis of recent p53-MDM2 inhibitors reported from 2011 to the present time, in this review, attentions are focused on the development of p53-MDM2 inhibitors published from 2011 to the present time.
    Current Medicinal Chemistry 11/2014; DOI:10.2174/0929867322666141128162557 · 3.72 Impact Factor
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    ABSTRACT: Protein/protein interactions (PPIs) are essential for all biological processes. Their role as central control switches and checkpoints in signaling and regulation makes their dysfunction an eminent cause of cancer and other diseases. Thus, a target-oriented intervention with PPIs, in particular by small molecules suitable for a pharmacological therapy, is the object of intense research. In the recent years, this research of PPIs yielded a number of low-molecular protein/protein interaction modulators (PPIMs). However, only a few PPIMs were identified by rational or structure-based considerations. The reason is that it is difficult to directly re-use well-established computational methods to identify ligands of conventional targets, such as enzymes, receptors, or transporters. Conventional targets naturally bind small molecules via pronounced complementary binding pockets. In contrast, many protein/protein interfaces (PPIfaces) are large and lack pronounced pockets. Thus, it is hard to find small molecules with an affinity and specificity that is adequate to displace one of the binding proteins. Nevertheless, the widespread discovery of (drug-like) PPIMs shows: these challenges can be overcome, and PPIs are not undruggable in general. The goal of this thesis was to develop a computational strategy for the rational identification of PPIMs, notably of NHR2 inhibitors, starting only with a protein/protein complex structure (PPI structure). This task subdivides into the four core themes of this thesis. First, I reviewed the knowledge about PPIs, PPIMs, the determinants of their interactions as well as computational methods for the identification of druggable sites and PPIMs. Second, I implemented a strategy that uses a PPI-structure based prediction of hot spots and transient pockets to guide a structure-based virtual screening. As a validation, I retrieved known PPIMs that bind to the PPIface of interleukin-2 from a large set of non-binders. Third, I analyzed the potential of teroxazoles as a new class of hydrophilic α-helix mimetics. These present side chains similar to α-helices and mimic a sequence pattern that has not yet been considered. Fourth, I identified the first micromolar inhibitors of the NHR2-mediated tetramerization of RUNX1-ETO (RE) from dimers, a prerequisite for the onset and maintenance of RE-dependent acute myeloid leukemia (RE-AML). Predicted tetramerization hot spots close to the largest pocket in the PPIface guided the computational identification of drug-like PPIMs. These PPIMs mimic NHR2 hot spots, aim at the PPIface, and inhibit dimer association as well as the proliferation of RE-dependent cells. These PPIMs are valuable as probes and tools to study the effects of NHR2 tetramerization and are an important step towards a personalized therapy of RE-AML. Most importantly, however, the presented strategy can well be the first step in any comparable structure-based endeavor to identify or design PPIMs, even in cases where only a PPI structure with a rather flat PPIface is known.
    10/2014, Degree: Dr. rer. nat. (PhD), Supervisor: Holger Gohlke