Erasca presents new RAS-targeting franchise data at AACR meeting

Erasca (ERAS) presented new preclinical data reinforcing the profiles of Erasca’s RAS-targeting franchise at the American Association for Cancer Research annual meeting in Chicago, Illinois. The company also presented potential examples of direct SHOC2 binders and modulators of SMP complex assembly, representing a new approach to block oncogenic RAS/MAPK pathway signaling. ERAS-0015 demonstrated favorable pharmacokinetic properties including longer residence time and greater tissue exposure that led to robust anti-tumor activity alone and in combination at doses lower than the leading pan-RAS molecular glue in development. ERAS-0015 is a pan-RAS molecular glue designed to shut down pathogenic signaling mediated by mutant and wildtype RAS by targeting RAS in the GTP-bound state. 8-21-fold greater cyclophilin A binding for ERAS-0015 vs. pan-RAS molecular glue comparator RMC-6236 ERAS-0015 dose-dependently formed a ternary complex with active state RAS and CypA, which blocks formation of additional downstream effector complexes. Potent inhibition of proliferation with ERAS-0015 across a panel of cell lines spanning diverse tumor tissues and RAS mutations. Preferential drug distribution into tumor tissues. Promising monotherapy and combination activity across multiple RAS mutant models. ERAS-4001 potentially has an expanded therapeutic index relative to pan-RAS inhibitors by selectively targeting both mutant and wildtype KRAS, leading to significant tumor growth inhibition alone and in combination. Selectively targeting both wildtype and oncogenic KRAS may address resistance mechanisms to mutant-selective KRAS inhibitors that are driven by WT KRAS activity. A potential pan-KRAS inhibitor, ERAS-4001 is a novel, highly potent pan-KRAS inhibitor that blocks mutant and WT KRAS, potentially offering improved tolerability relative to pan-RAS inhibitors by sparing NRAS and HRAS. ERAS-4001 selectively inhibited KRAS mutant enzymes and WT KRAS over WT HRAS and NRAS. ERAS-4001 inhibited 3D cell viability and proliferation in 13 G12X mutant and one wildtype KRAS amplified cell lines across indications with single digit nanomolar IC50s. Dose-dependent tumor growth inhibition and significant antitumor efficacy with ERAS-4001 monotherapy in KRAS mutant xenograft models. Robust tumor growth inhibition with ERAS-4001 plus anti-PD-1 or cetuximab in KRAS mutant models Promising antitumor monotherapy and combination activity across multiple KRAS mutant models. Identified inhibitors of SMP complex assembly via SHOC2 engagement, representing a potential new approach to attenuate RAS/MAPK pathway signaling. Genetic ablation or protein degradation of SHOC2 can sensitize RAS-driven cells to RAS/MAPK pathway inhibitors and prevent adaptive resistance. Identified two lead series that bind selectively to SHOC2 with low nanomolar affinity, interfere with SMP complex assembly, and inhibit the SMP complex’s phosphatase activity. To the company’s knowledge, these compounds represent the first examples of direct modulators of the SMP complex. Further optimization of SHOC2 binders for protein-protein inhibitors and degrader modalities is ongoing.