Abstract 3327: Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors

The non-receptor protein tyrosine phosphatase SHP2 (PTPN11) plays an important role in the regulation of RAS/MAPK signal transduction downstream of growth factor receptor activation. Loss of SHP2 activity suppresses tumor cell growth, making SHP2 a potential target for cancer therapy. Here we report...

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Veröffentlicht in:	Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.3327-3327
Hauptverfasser:	Williams, Bret, Taylor, Alexander, Orozco, Olivia, Owen, Christopher, Kelley, Elizabeth, Lescarbeau, Andre, Shortsleeves, Kelley, Kipp, Randy, Nguyen, Vy, Brophy, Erin, Wilbur, Jeremy, Tang, Yong, Lanzetta, David, Waters, Nigel, Smith, Sherri, Giordanetto, Fabrizio, Maragakis, Paul, Greismann, Jack, Willmore, Lindsay, Therrien, Eric, Xiao, Yang, Evangelista, Marie, Gerosa, Luca, Lin, Eva, Merchant, Mark, Arrazate, Alfonso, Chan, Emily, Larrocha, Pablo Sáenz-López, Chun, Stefan, Hunsaker, Thomas, Deshmukh, Gauri, Bowman, Christine M., Shaw, David E., Murcko, Mark, Padval, Mahesh, Walters, W Patrick, Watters, James, Bergstrom, Donald A.
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Sprache:	eng
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Zusammenfassung:	The non-receptor protein tyrosine phosphatase SHP2 (PTPN11) plays an important role in the regulation of RAS/MAPK signal transduction downstream of growth factor receptor activation. Loss of SHP2 activity suppresses tumor cell growth, making SHP2 a potential target for cancer therapy. Here we report the discovery of GDC-1971 (formerly RLY-1971), a highly potent, selective, and orally bioavailable small-molecule SHP2 inhibitor that stabilizes SHP2 in a closed, auto-inhibited conformation. GDC-1971 potently inhibits both wild-type SHP2 (IC50
ISSN:	1538-7445 1538-7445
DOI:	10.1158/1538-7445.AM2022-3327