BRSD-143 / Novartis - LARVOL DELTA

Lead Optimization of Multimutant KRAS Switch-II Pocket Macrocyclic Inhibitors via Isosteric Replacement to Improve ADME and Oral Exposure. (PubMed, J Med Chem) - "Starting from our internally discovered, potent panKRAS inhibitor BRSD-143 (1), we executed a targeted bioisosteric optimization of the naphthol and fluoropyrrolizidine motifs to preserve (or increase) KRAS pan-inhibitory potency while improving DMPK/ADME liabilities. These studies delivered 12 (BRSD-212), a highly potent and efficacious lead in which (2-azabicyclo[4.2.0]octan-6-yl)methanol (ABO) serves as a bioisostere for the widely deployed 2-fluoropyrrolizidine substituent. In parallel, replacement of the naphthol moiety with an indazole afforded 21, which demonstrated improved pharmacokinetic performance and ADME characteristics by mitigating glucuronidation-mediated clearance as the dominant metabolic pathway."

Journal • KRAS

Discovery and characterization of BRSD-143, an orally bioavailable panKRAS inhibitor (AACR 2025) - "In this study, direct comparison of panKRAS, panRAS, and KRAS G12D specific inhibitors suggested equivalent efficacy can be achieved by these different mechanisms. However, further studies are necessary to understand effects on the anti-tumor immune response and which compounds can be best combined with KRAS targeting inhibitors."

Late-breaking abstract • Colorectal Cancer • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • BCL2L1 • EGFR • HRAS • ITGAM • KRAS • NRAS