BRSD-143

BRSD-143 is an orally bioavailable, potent panKRAS inhibitor developed by Novartis. It targets the Switch II (SwII) pocket of KRAS, exhibiting low picomolar binding affinity for wild-type KRAS as well as a broad spectrum of KRAS mutants, including G12D, G12V, G12C, G12A, G12S, G13D, and Q61H. By inhibiting KRAS, BRSD-143 suppresses downstream MAPK signaling, as evidenced by the inhibition of pERK. Preclinical studies have demonstrated significant anti-tumor efficacy across various cell-derived xenograft models, including lung, colorectal, pancreatic, gastric, and leiomyosarcoma cancers. Additionally, BRSD-143 has been shown to modulate the tumor immune microenvironment by increasing T cell infiltration and promoting M1 macrophage polarization. It is being explored for its potential to synergize with other targeted therapies such as EGFR, PI3K, and YAP/TEAD inhibitors.