239 (PB119) - Preclinical efficacy of BDTX-4933, a brain penetrant MasterKey inhibitor targeting oncogenic BRAF Class I/II/III mutations

Abstract

Background: FDA-approved BRAF inhibitors target V600 (Class I) mutant monomers and are largely inactive against mutant BRAF dimers. These dimeric mutants found in many solid tumors including primary CNS tumors and brain metastases can drive RAS-independent (Class II) or RAS-dependent (Class III) oncogenic tumor growth. Furthermore, the approved BRAF inhibitors can induce paradoxical RAF activation that limits their activity. Although currently approved BRAF V600 mutation-selective inhibitors demonstrated efficacy in brain tumors and metastases when combined with MEK inhibitors in clinical trials, duration of response tends to be short partly due to limited BBB permeability.