Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.
作者： Hengmiao Cheng , Chunze Li , Simon Bailey , Sangita M. Baxi , Lance Goulet
DOI: 10.1021/ML300309H
关键词:
摘要: PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for structurally differentiated back-up candidate PF-04691502, which is currently phase I/II clinical trials treating solid tumors, lead optimization effort was carried out with tricyclic imidazo[1,5]naphthyridine series. Integration structure-based drug design physical properties-based yielded potent selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the series, both improved vitro potency addressed number ADMET issues including high metabolic clearance mediated by P450 aldehyde oxidase (AO), poor permeability, solubility. An empirical scaling tool developed predict human liver S9 assay data derivatives that were AO substrates.
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S. J. Shuttleworth, F. A. Silva, A. R.L. Cecil, C. D. Tomassi, T. J. Hill, F. I. Raynaud, P. A. Clarke, P. Workman, Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors Current Medicinal Chemistry. ,vol. 18, pp. 2686- 2714 ,(2011) , 10.2174/092986711796011229
Kevin D. Courtney, Ryan B. Corcoran, Jeffrey A. Engelman, The PI3K Pathway As Drug Target in Human Cancer Journal of Clinical Oncology. ,vol. 28, pp. 1075- 1083 ,(2010) , 10.1200/JCO.2009.25.3641
Jeffrey A. Engelman, Ji Luo, Lewis C. Cantley, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism Nature Reviews Genetics. ,vol. 7, pp. 606- 619 ,(2006) , 10.1038/NRG1879
Amy S. Rosen, Philippe Fournié, Mona Darwish, Philippe Danjou, Steven M. Troy, Zaleplon pharmacokinetics and absolute bioavailability. Biopharmaceutics & Drug Disposition. ,vol. 20, pp. 171- 175 ,(1999) , 10.1002/(SICI)1099-081X(199904)20:3<171::AID-BDD169>3.0.CO;2-K
B. Kaye, J. L. Offerman, J. L. Reid, H. L. Elliott, W. S. Hillis, A species difference in the presystemic metabolism of carbazeran in dog and man Xenobiotica. ,vol. 14, pp. 935- 945 ,(1984) , 10.3109/00498258409151492
Enrico Garattini, Mineko Terao, Increasing recognition of the importance of aldehyde oxidase in drug development and discovery Drug Metabolism Reviews. ,vol. 43, pp. 374- 386 ,(2011) , 10.3109/03602532.2011.560606
Aranapakam M. Venkatesan, Christoph M. Dehnhardt, Efren Delos Santos, Zecheng Chen, Osvaldo Dos Santos, Semiramis Ayral-Kaloustian, Gulnaz Khafizova, Natasja Brooijmans, Robert Mallon, Irwin Hollander, Larry Feldberg, Judy Lucas, Ker Yu, James Gibbons, Robert T. Abraham, Inder Chaudhary, Tarek S. Mansour, Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. Journal of Medicinal Chemistry. ,vol. 53, pp. 2636- 2645 ,(2010) , 10.1021/JM901830P
Deepak Dalvie, Chenghong Zhang, Weichao Chen, Teresa Smolarek, R. Scott Obach, Cho-Ming Loi, Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences. Drug Metabolism and Disposition. ,vol. 38, pp. 641- 654 ,(2010) , 10.1124/DMD.109.030783
R. Scott Obach, POTENT INHIBITION OF HUMAN LIVER ALDEHYDE OXIDASE BY RALOXIFENE Drug Metabolism and Disposition. ,vol. 32, pp. 89- 97 ,(2004) , 10.1124/DMD.32.1.89
Jing Yuan, Pramod P. Mehta, Min-Jean Yin, Shaoxian Sun, Aihua Zou, Jeffrey Chen, Kristina Rafidi, Zheng Feng, Jeffrey Nickel, Jon Engebretsen, Jill Hallin, Alessandra Blasina, Eric Zhang, Leslie Nguyen, Minghao Sun, Peter K. Vogt, Aileen McHarg, Hengmiao Cheng, James G. Christensen, Julie L.C. Kan, Shubha Bagrodia, PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity Molecular Cancer Therapeutics. ,vol. 10, pp. 2189- 2199 ,(2011) , 10.1158/1535-7163.MCT-11-0185