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

Abstract

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

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors

“…Analyses of available data revealed the importance of an indazole moiety as a privileged motif in the SWII pocket, able to form hydrogen bonds with the D69 side chain and filling a hydrophobic region formed by V103, I100, M72, and Y96 . Compound 1 (Figure A) was discovered from SAR exploration of a weakly active phenyl acrylamide hit identified from the focused screen.…”

“…Compound 21 showed 50% growth inhibition of NCI-H358 cells at a concentration of 18 nM, whereas a similar degree of growth inhibition for the non-KRAS G12C -dependent cell line NCI-H1437 (KRAS WT /MEK Q56P ) required a concentration of 4 μM, indicating high specificity for the target. Additional assessments of the selectivity of reversible binding of 21 to wild-type RAS isoforms, and its proteome-wide selectivity of covalent attachment, have been previously published …”

“…On the basis of the overall favorable preclinical profile and predicted human CL, 21 has been selected for clinical development as JDQ443, and we have recently reported early clinical data from a Phase Ib/II trial (showing the activity of JDQ443 against KRAS G12C -mutated tumors both as a monotherapy and in combination with the SHP2 inhibitor TNO155, along with preliminary exposure and safety data). , …”

“…Synthetic details for 1 , 2 , 8 , and JDQ443 ( 21 ), and for the probes used in the covalent competition assay described herein, have been previously reported . The preparation of 2 is included here to provide details on the isolation of the active eutomer 2a , and the preparation of JDQ443 is included for its use and the use of its precursors in the synthesis of the other KRAS G12C inhibitor compounds described here.…”

Small molecule inhibitors targeting the cancers

“…JDQ443 is a selective covalent inhibitor of KRAS G12C and forms novel interactions with the switch II pocket. 624 It showed potent antiproliferative activity in KRAS G12C‐mutated and KRAS G12C/H95 double mutated cell lines and is in clinical trials for KRAS G12C‐mutated tumors (NCT04699188 and NCT05132075). Prenylation of mutant RAS is the primary activator of downstream signaling.…”