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Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-06 , DOI: 10.1021/acs.jmedchem.9b02052 Jay B Fell 1 , John P Fischer 1 , Brian R Baer 1 , James F Blake 1 , Karyn Bouhana 1 , David M Briere 2 , Karin D Brown 1 , Laurence E Burgess 1 , Aaron C Burns 2 , Michael R Burkard 1 , Harrah Chiang 2 , Mark J Chicarelli 1 , Adam W Cook 1 , John J Gaudino 1 , Jill Hallin 2 , Lauren Hanson 1 , Dylan P Hartley 1 , Erik J Hicken 1 , Gary P Hingorani 1 , Ronald J Hinklin 1 , Macedonio J Mejia 1 , Peter Olson 2 , Jennifer N Otten 1 , Susan P Rhodes 1 , Martha E Rodriguez 1 , Pavel Savechenkov 1 , Darin J Smith 1 , Niranjan Sudhakar 2 , Francis X Sullivan 1 , Tony P Tang 1 , Guy P Vigers 1 , Lance Wollenberg 1 , James G Christensen 2 , Matthew A Marx 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-06 , DOI: 10.1021/acs.jmedchem.9b02052 Jay B Fell 1 , John P Fischer 1 , Brian R Baer 1 , James F Blake 1 , Karyn Bouhana 1 , David M Briere 2 , Karin D Brown 1 , Laurence E Burgess 1 , Aaron C Burns 2 , Michael R Burkard 1 , Harrah Chiang 2 , Mark J Chicarelli 1 , Adam W Cook 1 , John J Gaudino 1 , Jill Hallin 2 , Lauren Hanson 1 , Dylan P Hartley 1 , Erik J Hicken 1 , Gary P Hingorani 1 , Ronald J Hinklin 1 , Macedonio J Mejia 1 , Peter Olson 2 , Jennifer N Otten 1 , Susan P Rhodes 1 , Martha E Rodriguez 1 , Pavel Savechenkov 1 , Darin J Smith 1 , Niranjan Sudhakar 2 , Francis X Sullivan 1 , Tony P Tang 1 , Guy P Vigers 1 , Lance Wollenberg 1 , James G Christensen 2 , Matthew A Marx 2
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Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.
中文翻译：
鉴定临床开发候选药物MRTX849，一种共价的KRASG12C抑制剂，用于治疗癌症。
为了赶上药物开发失败，利益减弱和假定难以直接靶向KRAS的时代，新技术和战略正在帮助该目标的复兴。如先前报道，四氢吡啶并嘧啶被确定为KRAS G12C的不可逆共价抑制剂，它们结合在KRAS的switch-II口袋中并与半胱氨酸12形成共价键。使用基于结构的药物设计，结合集中的体外吸收，分布，代谢和排泄筛选方法，合成了类似物以增加该系列药物的效力并减少其代谢负担。临床开发候选药物MRTX849作为有效的选择性KRAS G12C共价抑制剂的发现 描述。
更新日期：2020-04-06
中文翻译：
鉴定临床开发候选药物MRTX849，一种共价的KRASG12C抑制剂，用于治疗癌症。
为了赶上药物开发失败，利益减弱和假定难以直接靶向KRAS的时代，新技术和战略正在帮助该目标的复兴。如先前报道，四氢吡啶并嘧啶被确定为KRAS G12C的不可逆共价抑制剂，它们结合在KRAS的switch-II口袋中并与半胱氨酸12形成共价键。使用基于结构的药物设计，结合集中的体外吸收，分布，代谢和排泄筛选方法，合成了类似物以增加该系列药物的效力并减少其代谢负担。临床开发候选药物MRTX849作为有效的选择性KRAS G12C共价抑制剂的发现 描述。
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