Structure-based drug design of novel, potent, and selective azabenzimidazoles (ABI) as ATR inhibitors

ACS Medicinal Chemistry Letters

Volumn 6, Issue 1, 2015, Pages 42-46

  Barsanti, Paul A ^a,b   Pan, Yue ^a   Lu, Yipin ^a   Jain, Rama ^a   Cox, Matthew ^a   Aversa, Robert J ^a   Dillon, Michael P ^a   Elling, Robert ^a   Hu, Cheng ^a   Jin, Xianming ^a   Knapp, Mark ^a   Lan, Jiong ^a   Ramurthy, Savithri ^a   Rudewicz, Patrick ^a   Setti, Lina ^a   Subramanian, Sharadha ^a   Mathur, Michelle ^a   Taricani, Lorena ^a   Thomas, George ^a   Xiao, Linda ^a   Yue, Qin ^a   more..

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b Nurix Inc   (United States)

Author keywords

aldehyde oxidase; ATR; CYP3A4 TDI; structure based drug design

Indexed keywords

ATR PROTEIN; AZABENZIMIDAZOLE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; BREAST CANCER RESISTANCE PROTEIN; CYTOCHROME P450 1A2; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; MULTIDRUG RESISTANCE PROTEIN; POTASSIUM CHANNEL HERG; PROTEIN SERINE THREONINE KINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CONFORMATIONAL TRANSITION; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG SOLUBILITY; HUMAN; HUMAN CELL; HYDROGEN BOND; IC50; LIMIT OF QUANTITATION; LIPOPHILICITY; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

EID: 84920747932     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml500352s     Document Type: Article

References (7)

1. Weinert, T. A. DNA damage checkpoint meets the cell cycle engine. Science 1997, 277, 1450-1451.
2. Foote, K. M.; Blades, K.; Cronin, A.; Fillery, S.; Guichard, S. S.; Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P. J.; McGuire, T. M.; Nissink, J. W. M.; Odedra, R.; Page, K.; Perkins, P.; Suleman, A.; Tam, K.; Thommes, P.; Broadhurst, R.; Wood, C. Discovery of 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J. Med. Chem. 2013, 56, 2125-2138.
3. Charrier, J. D.; Durrant, S. J.; Golec, J. M. C.; Kay, D. P.; Knegtel, R. M. A.; MacCormick, S.; Mortimore, M.; O'Donnell, M. E.; Pinder, J. L.; Reaper, P. M.; Rutherford, A. P.; Wang, P. S. H.; Young, S. C.; Pollard, J. R. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J. Med. Chem. 2011, 54, 2320-2330.
4. Garattini, E.; Terao, M. The role of aldehyde oxidase in drug metabolism. Expert Opin. Drug Metab. Toxicol. 2012, 8, 487-503.
5. Morrison, R. D.; Blobaum, A. L.; Byers, F. W.; Santomango, T. S.; Bridges, T. M.; Stec, D.; Brewer, K. A.; Sanchez-Ponce, R.; Corlew, M. M.; Rush, R.; Felts, A. S.; Manka, J.; Bates, B. S.; Venable, D. F.; Rodriguez, A. L.; Jones, C. K.; Niswender, C. M.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A.; Daniels, J. S. The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5. Drug Metab. Dispos. 2012, 40, 1834-1845.
6. Hollenberg, P. F.; Kent, U. M.; Bumpus, N. N. Mechanism-based inactivation of human cytochromes P450s: experimental characterization, reactive intermediates, and clinical implications. Chem. Res. Toxicol. 2008, 21, 189-205.
7. Safina, B. S.; Baker, S.; Baumgardner, M.; Blaney, P. M.; Chan, B. K.; Chen, Y.; Cartwright, M. W.; Castanedo, G.; Chabot, C.; Cheguillaume, A. J.; Goldsmith, P.; Goldstein, D. M.; Goyal, B.; Hancox, T.; Handa, R. K.; Iyer, P. S.; Kaur, J.; Kondru, R.; Kenny, J. R.; Krintel, S. L.; Li, J.; Lesnick, J.; Lucas, M. C.; Lewis, C.; Mukadam, S.; Murray, J.; Nadin, A. J.; Nonomiya, J.; Padilla, F.; Palmer, W. S.; Pang, J.; Pegg, N.; Price, S.; Reif, K.; Salphati, L.; Savy, P. A.; Seward, E. M.; Shuttleworth, S.; Sohal, S.; Sweeney, Z. K.; Tay, S.; Tivitmahaisoon, P.; Waszkowycz, B.; Wei, B.; Yue, Q.; Zhang, C.; Sutherin, D. P. Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition. J. Med. Chem. 2012, 55, 5887-5900.