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Ref Type Abstract
PMID
Authors Ng, P.Y. et al.
Title Preclinical efficacy of BDTX-4933, a brain penetrant MasterKey inhibitor targeting oncogenic BRAF Class I/II/III mutations
Journal Vol Issue Date Pages Journal Short Title
European Journal of Cancer 174 Supplement 1 2022
URL https://www.ejcancer.com/article/S0959-8049(22)01027-9/fulltext
Abstract Text 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. There remains a high unmet clinical need for a broad Class I/II/III BRAF inhibitor with high CNS penetrant activity for patients with RAF-dependent tumors carrying a broad spectrum of BRAF alterations. Materials and Methods: The MAP platform used NGS data and a proprietary machine-learning algorithm to predict and then validate the oncogenicity of previously uncharacterized groups of oncogenic BRAF mutations across Class I/II/III and to identify small molecule MasterKey drug candidates against this spectrum of mutations. Candidates were further optimized for brain penetration properties. Results: BDTX-4933 is a potent, selective, CNS penetrant BRAF Class I/ II/III mutation inhibitor that targets MAP-predicted oncogenic BRAF alterations while sparing wild type BRAF with >10-fold selectivity in cell proliferation assays. BDTX-4933 inhibits the RAF-MEK-ERK signaling pathway and cell proliferation across a panel of cancer cell lines endogenously expressing Class I/II/III mutations without paradoxical RAF activation. BDTX-4933 achieves target engagement, inhibiting the BRAF signaling pathway in in vivo models, and anti-tumor activity across tumor models representing all three classes of BRAF mutations including NSCLC and melanoma. Preclinical data shows that BDTX-4933 achieves high CNS exposure, and results in tumor growth inhibition and survival benefit in BRAF mutant intracranial models. Conclusions: BDTX-4933 has all the attributes of a best-in-class CNS penetrant BRAF inhibitor to address patients with and without CNS disease whose tumors express monomeric (Class I) or dimeric (Class II and III) BRAF mutants. BDTX-4933 achieves on-target inhibition of the RAF-MEK-ERK signaling pathway and anti-tumor activity in multiple preclinical tumor models, including intracranial models. IND-enabling studies for BDTX-4933 are underway.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF class 1 Advanced Solid Tumor predicted - sensitive BDTX-4933 Preclinical - Cell culture Actionable In a preclinical study, BDTX-4933 inhibited proliferation of cells expressing a BRAF class 1 mutation in culture (Eur J Cancer (2022), Vol 174, Supplement 1: S86). detail...
BRAF class 2 Advanced Solid Tumor predicted - sensitive BDTX-4933 Preclinical - Cell culture Actionable In a preclinical study, BDTX-4933 inhibited proliferation of cells expressing a BRAF class 2 mutation in culture (Eur J Cancer (2022), Vol 174, Supplement 1: S86). detail...
BRAF class 3 Advanced Solid Tumor predicted - sensitive BDTX-4933 Preclinical - Cell culture Actionable In a preclinical study, BDTX-4933 inhibited proliferation of cells expressing a BRAF class 3 mutation in culture (Eur J Cancer (2022), Vol 174, Supplement 1: S86). detail...