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Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-29 , DOI: 10.1021/acs.jmedchem.3c00483 Alexander M Taylor 1 , Bret R Williams 1 , Fabrizio Giordanetto 2 , Elizabeth H Kelley 1 , André Lescarbeau 1 , Kelley Shortsleeves 1 , Yong Tang 1 , W Patrick Walters 1 , Alfonso Arrazate 3 , Christine Bowman 3 , Erin Brophy 1 , Emily W Chan 3 , Gauri Deshmukh 3 , Jack B Greisman 2 , Thomas L Hunsaker 3 , D Randal Kipp 1 , Pablo Saenz Lopez-Larrocha 3 , Danilo Maddalo 3 , Iain J Martin 1 , Paul Maragakis 2 , Mark Merchant 3 , Mark Murcko 1 , Hunter Nisonoff 2 , Vi Nguyen 1 , Vy Nguyen 1 , Olivia Orozco 1 , Christopher Owen 1 , Levi Pierce 1 , Molly Schmidt 1 , David E Shaw 2, 4 , Sherri Smith 1 , Eric Therrien 5 , John C Tran 3 , Jim Watters 1 , Nigel J Waters 1 , Jeremy Wilbur 1 , Lindsay Willmore 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-29 , DOI: 10.1021/acs.jmedchem.3c00483 Alexander M Taylor 1 , Bret R Williams 1 , Fabrizio Giordanetto 2 , Elizabeth H Kelley 1 , André Lescarbeau 1 , Kelley Shortsleeves 1 , Yong Tang 1 , W Patrick Walters 1 , Alfonso Arrazate 3 , Christine Bowman 3 , Erin Brophy 1 , Emily W Chan 3 , Gauri Deshmukh 3 , Jack B Greisman 2 , Thomas L Hunsaker 3 , D Randal Kipp 1 , Pablo Saenz Lopez-Larrocha 3 , Danilo Maddalo 3 , Iain J Martin 1 , Paul Maragakis 2 , Mark Merchant 3 , Mark Murcko 1 , Hunter Nisonoff 2 , Vi Nguyen 1 , Vy Nguyen 1 , Olivia Orozco 1 , Christopher Owen 1 , Levi Pierce 1 , Molly Schmidt 1 , David E Shaw 2, 4 , Sherri Smith 1 , Eric Therrien 5 , John C Tran 3 , Jim Watters 1 , Nigel J Waters 1 , Jeremy Wilbur 1 , Lindsay Willmore 2
Affiliation
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Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.
中文翻译：
GDC-1971 (RLY-1971) 的鉴定，一种专为治疗实体瘤而设计的 SHP2 抑制剂
蛋白酪氨酸磷酸酶 SHP2 介导 RAS 驱动的 MAPK 信号传导，近年来已成为肿瘤学研究的一个靶点，既可用于单药治疗，也可与 KRAS 抑制剂联合治疗。我们被 SHP2 抑制的药理学潜力所吸引，特别是在最初观察到类药物化合物可以结合变构位点并强制酶处于封闭、非活性状态之后。在这里，我们描述了GDC-1971（以前称为 RLY-1971）的鉴定和表征，GDC-1971 是一种目前正在进行临床试验的 SHP2 抑制剂，与 KRAS G12C 抑制剂 divarasib (GDC-6036) 联合用于治疗由 KRAS G12C 突变驱动的实体瘤。
更新日期：2023-09-29
中文翻译：
GDC-1971 (RLY-1971) 的鉴定，一种专为治疗实体瘤而设计的 SHP2 抑制剂
蛋白酪氨酸磷酸酶 SHP2 介导 RAS 驱动的 MAPK 信号传导，近年来已成为肿瘤学研究的一个靶点，既可用于单药治疗，也可与 KRAS 抑制剂联合治疗。我们被 SHP2 抑制的药理学潜力所吸引，特别是在最初观察到类药物化合物可以结合变构位点并强制酶处于封闭、非活性状态之后。在这里，我们描述了GDC-1971（以前称为 RLY-1971）的鉴定和表征，GDC-1971 是一种目前正在进行临床试验的 SHP2 抑制剂，与 KRAS G12C 抑制剂 divarasib (GDC-6036) 联合用于治疗由 KRAS G12C 突变驱动的实体瘤。
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