Taylor Alexander M, Williams Bret R, Giordanetto Fabrizio, Kelley Elizabeth H, Lescarbeau André, Shortsleeves Kelley, Tang Yong, Walters W Patrick, Arrazate Alfonso, Bowman Christine, Brophy Erin, Chan Emily W, Deshmukh Gauri, Greisman Jack B, Hunsaker Thomas L, Kipp D Randal, Saenz Lopez-Larrocha Pablo, Maddalo Danilo, Martin Iain J, Maragakis Paul, Merchant Mark, Murcko Mark, Nisonoff Hunter, Nguyen Vi, Nguyen Vy, Orozco Olivia, Owen Christopher, Pierce Levi, Schmidt Molly, Shaw David E, Smith Sherri, Therrien Eric, Tran John C, Watters Jim, Waters Nigel J, Wilbur Jeremy, Willmore Lindsay
Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States.
D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States.
J Med Chem. 2023 Oct 12;66(19):13384-13399. doi: 10.1021/acs.jmedchem.3c00483. Epub 2023 Sep 29.
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 (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.
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领域备受关注的靶点，可用于单药治疗以及与KRAS抑制剂联合使用。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使该酶处于封闭的无活性状态之后。在此，我们描述了（原RLY-1971）的鉴定和特性，这是一种SHP2抑制剂，目前正在进行临床试验，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。
