Friday, April 15, 2022

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent and Selective, Covalent Oral Inhibitor of KRASG12C

Andreas Weiss1*, Edwige Lorthiois1*, Louise Barys1, Kim S. Beyer1, Claudio Bomio-Confaglia1, Heather Burks2, Xueying Chen3, Xiaoming Cui3, Ruben de Kanter1, Lekshmi Dharmarajan1, Carmine Fedele2, Marc Gerspacher1, Daniel Alexander Guthy1, Victoria Head 1, Ashley Jaeger2, Eloísa Jiménez Núñez 1, Jeffrey D Kearns2, Catherine Leblanc1, Sauveur-Michel Maira1, Jason Murphy2, Helen Oakman2, Nils Ostermann1, Johannes Ottl1, Pascal Rigollier1, Danielle Roman1, Christian Schnell1, Richard Sedrani1, Toshio Shimizu4, Rowan Stringer1, Andrea Vaupel1, Hans Voshol1, Peter Wessels5, Toni Widmer5, Rainer Wilcken1, Kun Xu3, Frederic Zecri2, Anna F. Farago2#, Simona Cotesta1# and Saskia M. Brachmann

Cancer Discov

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS 46 G12C-mutated cancers, though resistance emerges and additional strategies are needed to improve 47 outcomes. JDQ443 is a structurally unique, covalent inhibitor of GDP-bound KRASG12C that forms 48 novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular 49 signaling and demonstrates selective antiproliferative activity in KRAS G12C-mutated cell lines, 50 including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven 51 antitumor efficacy in KRAS G12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor 52 xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with SHP2, 53 MEK or CDK4/6 inhibitors. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is 54 maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. 55 JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both 56 strategies showing antitumor activity in patients with KRAS G12C-mutated tumors.   

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...