Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Autor:	Taylor AM; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Williams BR; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Giordanetto F; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States., Kelley EH; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Lescarbeau A; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Shortsleeves K; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Tang Y; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Walters WP; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Arrazate A; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Bowman C; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Brophy E; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Chan EW; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Deshmukh G; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Greisman JB; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States., Hunsaker TL; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Kipp DR; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Saenz Lopez-Larrocha P; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Maddalo D; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Martin IJ; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Maragakis P; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States., Merchant M; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Murcko M; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Nisonoff H; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States., Nguyen V; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Nguyen V; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Orozco O; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Owen C; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Pierce L; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Schmidt M; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Shaw DE; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States.; Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th St., New York, New York 10032, United States., Smith S; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Therrien E; Schrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United States., Tran JC; Genentech, Inc., 1 DNA Way Mailstop 258A, South San Francisco, California 94080-4990, United States., Watters J; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Waters NJ; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Wilbur J; Relay Therapeutics, Inc., 399 Binney St., Cambridge,, Massachusetts 02139, United States., Willmore L; D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Oct 12; Vol. 66 (19), pp. 13384-13399. Date of Electronic Publication: 2023 Sep 29.
DOI:	10.1021/acs.jmedchem.3c00483
Abstrakt:	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.
Databáze:	MEDLINE
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