Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b] pyridin-2-yl)pyridin-2-amines: Orally bioavailable, selective, and potent ATP-independent Akt inhibitors

Journal of Medicinal Chemistry

Volumn 55, Issue 11, 2012, Pages 5291-5310

  Ashwell, Mark A ^a   Lapierre, Jean Marc ^a   Brassard, Christopher ^a   Bresciano, Karen ^a   Bull, Cathy ^a   Cornell Kennon, Susan ^a   Eathiraj, Sudharshan ^a   France, Dennis S ^a   Hall, Terence ^a   Hill, Jason ^a   Kelleher, Eoin ^a   Khanapurkar, Sampada ^a   Kizer, Darin ^a   Koerner, Steffi ^a   Link, Jeff ^a   Liu, Yanbin ^a   Makhija, Sapna ^a   Moussa, Magdi ^a   Namdev, Nivedita ^a   Nguyen, Khanh ^a   Nicewonger, Robert ^a   Palma, Rocio ^a   Szwaya, Jeff ^a   Tandon, Manish ^a   Uppalapati, Uma ^a   Vensel, David ^a   Volak, Laurie P ^a   Volckova, Erika ^a   Westlund, Neil ^a   Wu, Hui ^a   Yang, Rui Yang ^a   Chan, Thomas C K ^a   more..

^a ARQULE INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; N [4 [2 (2 AMINOPYRIDIN 3 YL) 6 (PYRIDIN 3 YL) 3H IMIDAZO [4,5 B]PYRIDIN 3 YL]BENZYL]BENZAMIDE; N [4 [5 (3 ACETAMIDOPHENYL) 2 (2 AMINOPYRIDIN 3 YL) 3H IMIDAZO[4,5 B]PYRIDIN 3 YL]BENZYL)] 3 FLUOROBENZAMIDE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BINDING AFFINITY; BINDING COMPETITION; CANCER CELL; CELL ACTIVITY; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVATION; ENZYME INHIBITION; HUMAN; HUMAN CELL; HYDROPHOBICITY; IC 50; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SPACE; MOUSE; NONHUMAN; PROCESS OPTIMIZATION; PROTEIN BINDING; PROTEIN CONFORMATION; STRUCTURE ACTIVITY RELATION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADENOSINE TRIPHOSPHATE; ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CATALYTIC DOMAIN; CELL LINE, TUMOR; CELL PROLIFERATION; CRYSTALLOGRAPHY, X-RAY; HUMANS; IMIDAZOLES; MICE; MICROSOMES, LIVER; MODELS, MOLECULAR; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN CONFORMATION; PROTO-ONCOGENE PROTEINS C-AKT; PYRIDINES; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84862282122     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300276x     Document Type: Article

References (22)

1. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the Phosphoinositide 3-Kinase Pathway in Cancer Nat. Rev. Drug Discovery 2009, 8, 627-644
2. Lindsley, C. W. The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress towards Target Validation: A 2009 Update Curr. Top. Med. Chem. 2010, 10, 458-477
3. Fresno-Vara, J. A.; Casado, E.; de-Castro, J.; Cejas, P.; Belda-Iniesta, C.; Gonzalez-Baron, M. PI3K/Akt Signalling Pathways and Cancer Cancer Treat. Rev. 2004, 30, 193-204
4. Collins, I. Targeting Small-Molecule Inhibitors of Protein Kinase B as Anticancer Agents Anti-Cancer Agents Med. Chem. 2009, 9, 32-50
5. Hirai, H.; Sootome, H.; Nakatsuru, Y.; Miyama, K.; Taguchi, S.; Tsujioka, K.; Ueno, Y.; Hatch, H.; Majumder, P. K.; Pan, B.-S.; Kotani, H. MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs in Vitro and in Vivo Mol. Cancer Ther. 2010, 9, 1956-1967
6. Eathiraj, S.; Palma, R.; Volckova, E.; Hirschi, M.; France, D. S.; Ashwell, M. A.; Chan, T. C. K. Discovery of a Novel Mode of Protein Kinase Inhibition Characterized by the Mechanism of Inhibition of Human Mesenchymal-Epithelial Transcription Factor (c-Met) Protein Autophosphorylation by ARQ 197 J. Biol. Chem. 2011, 286, 20666-20676
7. Eathiraj, S.; Palma, R.; Hirschi, M.; Volckova, E.; Enkeleda, N.; Castro, J.; Chen, C.-R.; Chan, T. C. K.; France, D. S.; Ashwell, M. A. A Novel Mode of Protein Kinase Inhibition Exploiting Hydrophobic Motifs of Autoinhibited Kinases J. Biol. Chem. 2011, 286, 20677-20687
8. Calleja, V.; Alcor, D.; Laguerre, M.; Park, J.; Vojnovic, B.; Hemmings, B. A.; Downward, J.; Parker, P. J.; Larijani, B. Intramolecular and Intermolecular Interactions of Protein Kinase B Define Its Activation in Vivo PLoS Biol. 2007, 5, e95
9. Huang, X.; Begley, M.; Morgenstern, K. A.; Gu, Y.; Rose, P.; Zhao, H.; Zhu, X. Crystal Structure of an Inactive Akt2 Kinase Domain Structure 2003, 11, 21-30
10. Muckenschnabel, I.; Falchetto, R.; Mayr, L. M.; Filipuzzi, I. SpeedScreen: Label-Free Liquid Chromatography-Mass Spectrometry-Based High-Throughput Screening for the Discovery of Orphan Protein Ligands Anal. Biochem. 2004, 324, 241-249
11. Lo, M. C.; Aulabaugh, A.; Jin, G.; Cowling, R.; Bard, J.; Malamas, M.; Ellestad, G. Evaluation of Fluoresence-Based Thermal Shift Assays for Hit Identification in Drug Discovery Anal. Biochem. 2004, 332, 153-159
12. Pantoliano, M.; W., Petrella, E. C.; Kwasnoski, J. D.; Lobanov, V. S.; Myslik, J.; Graf, E.; Carver, T.; Asel, E.; Springer, B. A.; Lane, P.; Salemme, F. R. High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery J. Biomol. Screening 2001, 6, 429-440
13. Nordin, H.; Jungnelius, M.; Karlsson, R.; Karlsson, O. P. Kinetic Studies of Small Molecule Interactions with Protein Kinases Using Biosensor Technology Anal. Biochem. 2005, 340, 359-368
14. Bozulic, L.; Hemmings, B. A. PIKKing on PKB: Regulation of PKB Activity by Phosphorylation Curr. Opin. Cell Biol. 2009, 21, 256-261
15. Chang, L. C. W.; Künzel, J. K. F. D.; Mulder-Krieger, T.; Westerhout, J.; Spangenberg, T.; Brussee, J.; IJzerman, A. P. 2,6,8-Trisubstituted 1-Deazapurines as Adenosine Receptor Antagonists J. Med. Chem. 2007, 50, 828-834
16. Hu, B.; Jetter, J.; Kaufman, D.; Singhaus, R.; Bernotas, R.; Unwalla, R.; Quinet, E.; Savio, D.; Halpern, A.; Basso, M.; Keith, J.; Clerin, V.; Chen, L.; Qiang-Yuan Liu, Q.-Y.; Feingold, I.; Huselton, C.; Azam, F.; Goos-Nilsson, A.; Wilhelmsson, A.; Nambib, P.; Wrobela, J. Further Modification on Phenyl Acetic Acid Based Quinolines as Liver X Receptor Modulators Bioorg. Med. Chem. 2007, 15, 3321-3333
17. Ben-zeev, E.; Chen, D.; Fichman, M.; Ghosh, S.; Koerner, S.; Lin, J.; Marantz, Y.; Melendez, R.; Mohanty, P.; Shacham, S.; Zhang, Z. Carboxamide Compounds as Chemokine Receptor Agonists. PCT WO2009/076512 A1, 2009.
18. Luo, Y.; Shoemaker, A. R.; Liu, X.; Woods, K. W.; Thomas, S. A.; de Jong, R.; Han, E. K.; Li, T.; Stoll, V. S.; Powlas, J. A.; Oleksijew, A.; Mitten, M. J.; Shi, Y.; Guan, R.; McGonigal, T. P.; Klinghofer, V.; Johnson, E. F.; Leverson, J. D.; Bouska, J. J.; Mamo, M.; Smith, R. A.; Gramling-Evans, E. E.; Zinker, B. A.; Mika, A. K.; Nguyen, P. T.; Oltersdorf, T.; Rosenbert, S. H.; Li, Q.; Giranda, V. L. Potent and Selective Inhibitors of Akt Kinases Slow the Progress of Tumors in Vivo Mol. Cancer Ther. 2005, 4, 977-986
19. Ashwell, M. A.; Palma, R.; Eathiraj, S. Use of Crystal Structures of Kinase Complexes with Inhibitors in the Design of Novel Inhibitor Drugs. US 7960134, 2011.
20. Kovacina, K. S.; Park, G. Y.; Bae, S. S.; Guzzetta, A. W.; Schaefer, E.; Birnbaum, M. J.; Roth, R. A. Identification of a Proline-Rich Akt Substrate as a 14-3-3 Binding Partner J. Biol. Chem. 2003, 278, 10189-10194
21. Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J. R.; Huber, H. E.; Duggan, M. E. Allosteric Akt (PKB) Inhibitors: Discovery and SAR Isozyme Selective Inhibitors Bioorg. Med. Chem. Lett. 2005, 15, 761-764
22. Wu, W.-I.; Voegtli, W. C.; Sturgis, H. L.; Dizon, F. P.; Vigers, G. P. A.; Brandhuber, B. J. Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition PLoS One 2010, 5 (9) e12913