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Gui-Dong Zhu,
Jianchun Gong,
Viraj B Gandhi,
Xuesong Liu,
Yan Shi,
Eric F Johnson,
Cherrie K Donawho,
Paul A Ellis,
Jennifer J Bouska,
Donald J Osterling,
Amanda M Olson,
Chang Park,
Yan Luo,
Alexander Shoemaker,
Vincent L Giranda,
Thomas D Penning
[show abstract]
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ABSTRACT: PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).
Bioorganic & medicinal chemistry 06/2012; 20(15):4635-45. · 2.82 Impact Factor
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Thomas D Penning, Gui-Dong Zhu,
Jianchun Gong,
Sheela Thomas,
Viraj B Gandhi,
Xuesong Liu,
Yan Shi,
Vered Klinghofer,
Eric F Johnson,
Chang H Park, [......],
Fritz G Buchanan,
Gail T Bukofzer,
Luis E Rodriguez,
Velitchka Bontcheva-Diaz,
Jennifer J Bouska,
Donald J Osterling,
Amanda M Olson,
Kennan C Marsh,
Yan Luo,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
Journal of Medicinal Chemistry 03/2010; 53(8):3142-53. · 4.80 Impact Factor
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[show abstract]
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ABSTRACT: Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1023-6. · 2.65 Impact Factor
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Joann P Palma,
Yi-Chun Wang,
Luis E Rodriguez,
Debra Montgomery,
Paul A Ellis,
Gail Bukofzer,
Amanda Niquette,
Xuesong Liu,
Yan Shi,
Loren Lasko, Gui-Dong Zhu,
Thomas D Penning,
Vincent L Giranda,
Saul H Rosenberg,
David J Frost,
Cherrie K Donawho
[show abstract]
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ABSTRACT: ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ.
ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT).
Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ.
Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
Clinical Cancer Research 12/2009; 15(23):7277-90. · 7.74 Impact Factor
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Xuesong Liu,
Edward K Han,
Mark Anderson,
Yan Shi,
Dimitri Semizarov,
Gang Wang,
Thomas McGonigal,
Lisa Roberts,
Loren Lasko,
Joann Palma, Gui-Dong Zhu,
Thomas Penning,
Saul Rosenberg,
Vincent L Giranda,
Yan Luo,
Joel Leverson,
Eric F Johnson,
Alexander R Shoemaker
[show abstract]
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ABSTRACT: Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. Gain of DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that is activated by DNA damage and plays a critical role in base excision repair. Inhibition of PARP represents an attractive approach for the treatment of cancer. Previously, we have described the discovery and characterization of a potent PARP inhibitor, ABT-888. ABT-888 potentiates the activity of DNA-damaging agents such as temozolomide (TMZ) in a variety of preclinical models. We report here the generation of HCT116 cells resistant to treatment with TMZ and ABT-888 (HCT116R cells). HCT116R cells exhibit decreased H2AX phosphorylation in response to treatment with TMZ and ABT-888 relative to parental HCT116 cells. Microarray and Western blot studies indicate that HCT116R cells have decreased PARP-1 and elevated Rad51 expression levels. HCT116R cells are dependent on Rad51 for proliferation and survival, as shown by inhibition of proliferation and induction of apoptosis upon treatment with Rad51 small interfering RNA. In addition, HCT116R cells are more resistant to radiation than the parental HCT116 cells. Our study suggests that cancer cells upregulate the homologous recombination DNA repair pathway to compensate for the loss of base excision repair, which may account for the observed resistance to treatment with TMZ and ABT-888.
Molecular Cancer Research 10/2009; 7(10):1686-92. · 4.29 Impact Factor
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ABSTRACT: Treatment of 3,5-dibromo- or 3,5-dichloro-pyridine-4-carboxaldehyde 2 with one equivalent of methyl thioglycolate, followed by exposure to base, provided 4-bromo- or 4-chloro-thieno[2,3-c]pyridine-2-carboxylate 4 in good yields. Oxidation of the thieno[2,3-c]pyridine scaffold such as 7 with mCPBA, followed by treatment with POBr3, introduced a bromine exclusively at the 7-position of the heterocycle. The 4- or 7-bromide of the thienopyridines readily underwent Suzuki, Stille coupling, and Buchwald amination reactions, to afford 4- or 7-substituted analogs 6 or 11. The 2-carboxylate of 4b or 12 was smoothly removed through saponification and decarboxylation to furnish 15 or 16. Deprotonation of the thienopyridine at C-2 position, followed by trapping with trimethyltin chloride, afforded a 2-stannyl analog, which was readily converted to other C-2 derivatives via Stille reaction.
Journal of Heterocyclic Chemistry 03/2009; 45(1):91 - 96. · 1.22 Impact Factor
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Thomas D Penning, Gui-Dong Zhu,
Viraj B Gandhi,
Jianchun Gong,
Xuesong Liu,
Yan Shi,
Vered Klinghofer,
Eric F Johnson,
Cherrie K Donawho,
David J Frost,
Velitchka Bontcheva-Diaz,
Jennifer J Bouska,
Donald J Osterling,
Amanda M Olson,
Kennan C Marsh,
Yan Luo,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.
Journal of Medicinal Chemistry 02/2009; 52(2):514-23. · 4.80 Impact Factor
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Xuesong Liu,
Yan Shi,
Ran Guan,
Cherrie Donawho,
Yanping Luo,
Joann Palma, Gui-Dong Zhu,
Eric F Johnson,
Luis E Rodriguez,
Nayereh Ghoreishi-Haack,
Ken Jarvis,
Vincent P Hradil,
Milagros Colon-Lopez,
Bryan F Cox,
Vered Klinghofer,
Thomas Penning,
Saul H Rosenberg,
David Frost,
Vincent L Giranda,
Yan Luo
[show abstract]
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ABSTRACT: Poly(ADP-ribose) polymerase (PARP) senses DNA breaks and facilitates DNA repair via the polyADP-ribosylation of various DNA binding and repair proteins. We explored the mechanism of potentiation of temozolomide cytotoxicity by the PARP inhibitor ABT-888. We showed that cells treated with temozolomide need to be exposed to ABT-888 for at least 17 to 24 hours to achieve maximal cytotoxicity. The extent of cytotoxicity correlates with the level of double-stranded DNA breaks as indicated by gammaH2AX levels. In synchronized cells, damaging DNA with temozolomide in the presence of ABT-888 during the S phase generated high levels of double-stranded breaks, presumably because the single-stranded DNA breaks resulting from the cleavage of the methylated nucleotides were converted into double-stranded breaks through DNA replication. As a result, treatment of temozolomide and ABT-888 during the S phase leads to higher levels of cytotoxicity. ABT-888 inhibits poly(ADP-ribose) formation in vivo and enhances tumor growth inhibition by temozolomide in multiple models. ABT-888 is well tolerated in animal models. ABT-888 is currently in clinical trials in combination with temozolomide.
Molecular Cancer Research 11/2008; 6(10):1621-9. · 4.29 Impact Factor
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Gui-Dong Zhu,
Viraj B Gandhi,
Jianchun Gong,
Sheela Thomas,
Yan Luo,
Xuesong Liu,
Yan Shi,
Vered Klinghofer,
Eric F Johnson,
David Frost,
Cherrie Donawho,
Ken Jarvis,
Jennifer Bouska,
Kennan C Marsh,
Saul H Rosenberg,
Vincent L Giranda,
Thomas D Penning
[show abstract]
[hide abstract]
ABSTRACT: Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):3955-8. · 2.65 Impact Factor
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Thomas D Penning, Gui-Dong Zhu,
Viraj B Gandhi,
Jianchun Gong,
Sheela Thomas,
Wilfried Lubisch,
Roland Grandel,
Wolfgang Wernet,
Chang H Park,
Elizabeth H Fry, [......],
Eric F Johnson,
Cherrie K Donawho,
David J Frost,
Velitchka Bontcheva-Diaz,
Jennifer J Bouska,
Amanda M Olson,
Kennan C Marsh,
Yan Luo,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Bioorganic & medicinal chemistry 06/2008; 16(14):6965-75. · 2.82 Impact Factor
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ABSTRACT: Majority of chemotherapeutic agents inhibit tumor growth by inducing apoptosis or necrosis. The DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), kills cells by necrosis through massive production of DNA strand breaks and subsequent over-activation of PARP. Inhibition of PARP, either through PARP1 genetic ablation or through small molecule PARP inhibitors, protected MNNG-induced cell death in certain cell types including MEF and primary cortical cultures. We report here that a potent PARP inhibitor, ABT-888, facilitates the induction of apoptotic cell death in HeLa cells treated with MNNG. Although the release of cytochrome c from mitochondria to cytosol was observed in HeLa cells treated with either MNNG alone or the combination of MNNG and ABT-888 (MNNG/ABT-888), apoptosis is observed only in HeLa cells treated with MNNG/ABT-888. Bcl-2 family proteins regulate the release of cytochrome c. Downregulation of Bax and Bak by their corresponding siRNAs or overexpression of Bcl-xl inhibited the release of cytochrome c from mitochondria to cytosol, and inhibited apoptosis induced by MNNG/ABT-888. Further examination indicates that ATP concentration is greatly reduced in HeLa cells treated with MNNG alone, but not in HeLa cells treated with MNNG/ABT-888. Reduction of ATP concentration by F0F1-ATP synthase inhibitor oligomycin A renders HeLa cells resistant to the apoptosis induction by treatment with MNNG/ABT-888. Unlike in HeLa cells, ABT-888 protected MNNG induced cell death in normal human fibroblasts. Our study provides evidence that PARP activity determines the fate of HeLa cells by regulating the level of ATP after treatment with MNNG.
Cancer biology & therapy 04/2008; 7(6):934-41. · 2.64 Impact Factor
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Gui-Dong Zhu,
Viraj B Gandhi,
Jianchun Gong,
Sheela Thomas,
Keith W Woods,
Xiaohong Song,
Tongmei Li,
R Bruce Diebold,
Yan Luo,
Xuesong Liu, [......],
Vincent S Stoll,
Mulugeta Mamo,
James Polakowski,
Thomas J Campbell,
Ruth L Martin,
Gary A Gintant,
Thomas D Penning,
Qun Li,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
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ABSTRACT: Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
Journal of Medicinal Chemistry 07/2007; 50(13):2990-3003. · 5.25 Impact Factor
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Cherrie K Donawho,
Yan Luo,
Yanping Luo,
Thomas D Penning,
Joy L Bauch,
Jennifer J Bouska,
Velitchka D Bontcheva-Diaz,
Bryan F Cox,
Theodore L DeWeese,
Larry E Dillehay, [......],
Amanda M Olson,
Joann P Palma,
Luis E Rodriguez,
Yan Shi,
Jason A Stavropoulos,
Alan C Tsurutani, Gui-Dong Zhu,
Saul H Rosenberg,
Vincent L Giranda,
David J Frost
[show abstract]
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ABSTRACT: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.
In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.
ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.
ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
Clinical Cancer Research 06/2007; 13(9):2728-37. · 7.74 Impact Factor
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Gui-Dong Zhu,
Jianchun Gong,
Viraj B Gandhi,
Keith Woods,
Yan Luo,
Xuesong Liu,
Ran Guan,
Vered Klinghofer,
Eric F Johnson,
Vincent S Stoll,
Mulugeta Mamo,
Qun Li,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.
Bioorganic & Medicinal Chemistry 04/2007; 15(6):2441-52. · 2.92 Impact Factor
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Keith W Woods,
John P Fischer,
Akiyo Claiborne,
Tongmei Li,
Sheela A Thomas, Gui-Dong Zhu,
Robert B Diebold,
Xuesong Liu,
Yan Shi,
Vered Klinghofer, [......],
Shayna R Magnone,
Eric F Johnson,
Jennifer J Bouska,
Amanda M Olson,
Ron de Jong,
Tilman Oltersdorf,
Yan Luo,
Saul H Rosenberg,
Vincent L Giranda,
Qun Li
[show abstract]
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ABSTRACT: A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
Bioorganic & Medicinal Chemistry 11/2006; 14(20):6832-46. · 2.92 Impact Factor
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Gui-Dong Zhu,
Viraj B Gandhi,
Jianchun Gong,
Yan Luo,
Xuesong Liu,
Yan Shi,
Ran Guan,
Shayna R Magnone,
Vered Klinghofer,
Eric F Johnson,
Jennifer Bouska,
Alexander Shoemaker,
Anatol Oleksijew,
Ken Jarvis,
Chang Park,
Ron De Jong,
Tilman Oltersdorf,
Qun Li,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.
Bioorganic & Medicinal Chemistry Letters 08/2006; 16(13):3424-9. · 2.55 Impact Factor
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Gui-Dong Zhu,
Jianchun Gong,
Akiyo Claiborne,
Keith W Woods,
Viraj B Gandhi,
Sheela Thomas,
Yan Luo,
Xuesong Liu,
Yan Shi,
Ran Guan, [......],
Eric F Johnson,
Jennifer Bouska,
Alexander Shoemaker,
Anatol Oleksijew,
Vincent S Stoll,
Ron De Jong,
Tilman Oltersdorf,
Qun Li,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
Bioorganic & Medicinal Chemistry Letters 06/2006; 16(12):3150-5. · 2.55 Impact Factor
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Qun Li,
Keith W Woods,
Sheela Thomas, Gui-Dong Zhu,
Garrick Packard,
John Fisher,
Tongmei Li,
Jianchun Gong,
Jurgen Dinges,
Xiaohong Song, [......],
Eric F Johnson,
Yan Shi,
Xuesong Liu,
Vered Klinghofer,
Ron Des Jong,
Tilman Oltersdorf,
Vincent S Stoll,
Clarissa G Jakob,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.
Bioorganic & Medicinal Chemistry Letters 05/2006; 16(7):2000-7. · 2.55 Impact Factor
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Qun Li,
Tongmei Li, Gui-Dong Zhu,
Jianchun Gong,
Akiyo Claibone,
Chris Dalton,
Yan Luo,
Eric F Johnson,
Yan Shi,
Xuesong Liu, [......],
Joy L Bauch,
Kennan C Marsh,
Jennifer J Bouska,
Shannon Arries,
Ron De Jong,
Tilman Oltersdorf,
Vincent S Stoll,
Clarissa G Jakob,
Saul H Rosenberg,
Vincent L Giranda
[show abstract]
[hide abstract]
ABSTRACT: A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1679-85. · 2.55 Impact Factor
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[show abstract]
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ABSTRACT: Over the past decade, protein kinases have emerged as a group of molecular targets with the potential to be "cancer-specific", allowing the selective targeting of cancer cells versus normal cells. These selective anticancer drugs would eliminate the cytotoxic side effects that are associated with conventional cancer chemotherapy. This article will focus on two emerging and less-explored protein serine/threonine kinase targets: PKB/Akt and checkpoint kinase 1 (Chk1). Protein kinase B/Akts are a group of serine/threonine kinases that are overexpressed in a variety of human tumors. An Akt inhibitor would target the imbalance of pro-versus anti-apoptosis regulation in cancerous as compared to healthy cells. Thus, a greater therapeutic window than conventional cytotoxic chemotherapy is expected. Cell-cycle checkpoints have become attractive targets since some of them, such as the G1/S checkpoint, are defective in most tumor cells. Inhibition of one or more of the remaining checkpoint(s) could make cancerous cells more sensitive than healthy cells toward DNA damaging agents or radiation therapy. Among the checkpoint kinases, Chk1 appears to be an attractive molecular target. Chk1 blocks the activation of the Cdc2-cyclin B kinase complex, and hence entry into mitosis, by disrupting the translocation of the phosphatase Cdc25C from the cyotoplasm to the nucleus. A limited number of small molecule inhibitors in this emerging field and their mode of action will be reviewed.
Current Topics in Medicinal Chemistry 10/2002; 2(9):939-71. · 4.17 Impact Factor
