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Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-24 , DOI: 10.1021/acs.jmedchem.0c01652 Hengmiao Cheng 1 , Suvi T. M. Orr 1 , Simon Bailey 1 , Alexei Brooun 1 , Ping Chen 1 , Judith G. Deal 1 , Yali L. Deng 1 , Martin P. Edwards 1 , Gary M. Gallego 1 , Neil Grodsky 1 , Buwen Huang 1 , Mehran Jalaie 1 , Stephen Kaiser 1 , Robert S. Kania 1 , Susan E. Kephart 1 , Jennifer Lafontaine 1 , Martha A. Ornelas 1 , Mason Pairish 1 , Simon Planken 1 , Hong Shen 1 , Scott Sutton 1 , Luke Zehnder 1 , Chau D. Almaden 1 , Shubha Bagrodia 1 , Matthew D. Falk 1 , Hovhannes J. Gukasyan 1 , Caroline Ho 1 , Xiaolin Kang 1 , Rachel E. Kosa 1 , Ling Liu 1 , Mary E. Spilker 1 , Sergei Timofeevski 1 , Ravi Visswanathan 1 , Zhenxiong Wang 1 , Fanxiu Meng 2 , Shijian Ren 2 , Li Shao 2 , Feng Xu 2 , John C. Kath 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-24 , DOI: 10.1021/acs.jmedchem.0c01652 Hengmiao Cheng 1 , Suvi T. M. Orr 1 , Simon Bailey 1 , Alexei Brooun 1 , Ping Chen 1 , Judith G. Deal 1 , Yali L. Deng 1 , Martin P. Edwards 1 , Gary M. Gallego 1 , Neil Grodsky 1 , Buwen Huang 1 , Mehran Jalaie 1 , Stephen Kaiser 1 , Robert S. Kania 1 , Susan E. Kephart 1 , Jennifer Lafontaine 1 , Martha A. Ornelas 1 , Mason Pairish 1 , Simon Planken 1 , Hong Shen 1 , Scott Sutton 1 , Luke Zehnder 1 , Chau D. Almaden 1 , Shubha Bagrodia 1 , Matthew D. Falk 1 , Hovhannes J. Gukasyan 1 , Caroline Ho 1 , Xiaolin Kang 1 , Rachel E. Kosa 1 , Ling Liu 1 , Mary E. Spilker 1 , Sergei Timofeevski 1 , Ravi Visswanathan 1 , Zhenxiong Wang 1 , Fanxiu Meng 2 , Shijian Ren 2 , Li Shao 2 , Feng Xu 2 , John C. Kath 1
Affiliation
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The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.
中文翻译：
PI3Kα-选择性抑制剂的基于结构的药物设计和合成（PF-06843195）
雷帕霉素的磷酸肌醇3-激酶（PI3K）/哺乳动物靶标（mTOR）信号通路是人类癌症中经常失调的通路，而PI3Kα是人类癌症中最频繁突变的激酶之一。PI3Kα选择性抑制剂可能为患者避免与广泛抑制I类PI3K家族相关的副作用提供了机会。在这里，我们描述了我们通过基于结构的药物设计（SBDD）和计算分析发现PI3Kα选择性抑制剂的努力。一系列新化合物，例如2,2-二氟乙基（3 S）-3-{[2'-氨基-5-氟-2-（吗啉-4-基）-4,5'-联嘧啶-6-氨基] -3-（羟甲基）吡咯烷-1-羧酸酯（1）（PF-06843195），发现具有高PI3Kα效能，独特的PI3K同工型和mTOR选择性。我们在这里描述导致1发现的设计和综合程序的详细信息。
更新日期：2021-01-14
中文翻译：
PI3Kα-选择性抑制剂的基于结构的药物设计和合成（PF-06843195）
雷帕霉素的磷酸肌醇3-激酶（PI3K）/哺乳动物靶标（mTOR）信号通路是人类癌症中经常失调的通路，而PI3Kα是人类癌症中最频繁突变的激酶之一。PI3Kα选择性抑制剂可能为患者避免与广泛抑制I类PI3K家族相关的副作用提供了机会。在这里，我们描述了我们通过基于结构的药物设计（SBDD）和计算分析发现PI3Kα选择性抑制剂的努力。一系列新化合物，例如2,2-二氟乙基（3 S）-3-{[2'-氨基-5-氟-2-（吗啉-4-基）-4,5'-联嘧啶-6-氨基] -3-（羟甲基）吡咯烷-1-羧酸酯（1）（PF-06843195），发现具有高PI3Kα效能，独特的PI3K同工型和mTOR选择性。我们在这里描述导致1发现的设计和综合程序的详细信息。
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