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Ref Type Abstract
PMID
Authors Stacie L. Bulfer; Bertrand Le Bourdonnec; Jeffery D. Zwicker; Yu Mi Ahn; Gada Al-Ani; Hikmat Al-Hashimi; Chase Crawley; Kristin M. Elliott; Saqib Faisal; Andrew M. Harned; Cale L. Heiniger; Molly M. Hood; Salim Javed; Michael Kennedy; Joshua W. Large; Cynthia B. Leary; Wei-Ping Lu; Kylie Luther; Max D. Petty; Hunter R. Picard; Justin T. Proto; Yeni K. Romero; Forrest A. Stanley; Kristen L. Stoltz; Daniel C. Tanner; Hanumaiah Telikepalli; Mary J. Timson; Lakshminarayana Vogeti; Subha Vogeti; Sihyung Yang; Lexy H. Zhong; Bryan D. Smith; Daniel L. Flynn
Title Abstract 4045: DCC-3084, a RAF dimer inhibitor, broadly inhibits BRAF class I, II, III, BRAF fusions, and RAS-driven solid tumors leading to tumor regression in preclinical models
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 83 7_Supplement April 1, 2023
URL https://aacrjournals.org/cancerres/article/83/7_Supplement/4045/724673/Abstract-4045-DCC-3084-a-RAF-dimer-inhibitor
Abstract Text Background: Mutations in the RAS/MAPK pathway are a frequent driver of cancer, with oncogenic RAS or RAF mutations occurring in >30% of all cancers. First generation BRAF inhibitors are approved for use for tumors with Class I BRAF mutations (V600X). However, these drugs are not efficacious in RAF dimer mutant and RAS mutant cancers due to paradoxical activation of RAF dimers. Herein, we describe DCC-3084, a potent and selective investigational Switch Control inhibitor of BRAF and CRAF kinase dimers that targets Class I, II and III BRAF mutations, BRAF fusions, and BRAF/CRAF heterodimers. DCC-3084 combines with inhibitors of additional nodes in the MAPK pathway to potentially target a large unmet medical need in RAS and RAF mutant cancers. Methods: Inhibition of RAF kinases, including off-rate analysis, was measured using recombinant enzymes. X-ray crystallography was used for structure-based drug design. Cellular proliferation was measured using resazurin to monitor cell viability. Synergy in cells was measured using BLISS scores and curve shift analysis. Inhibition of ERK or RSK phosphorylation was measured by AlphaLISA or ELISA. Pharmacokinetics (PK) in the plasma, brain and CSF compartments were measured following oral dosing in Wistar rats. RAF and RAS mutant mouse xenograft models were used to assess PK, pharmacodynamics (PD), and efficacy. Results: DCC-3084 is a potent and selective Switch Control inhibitor of RAF dimers that was designed to target Class I, II, III BRAF mutants, BRAF fusions, and BRAF/CRAF heterodimers. DCC-3084 inhibits BRAF and CRAF, exhibiting slow off-rates (t1/2 >20 hr). Potent single-agent inhibition of MAPK pathway signaling and cellular proliferation was observed in a wide range of Class I, II, III BRAF and BRAF fusion altered cell lines. Synergy was observed in combination with inhibitors of other nodes in the RAS/MAPK pathway in RAS mutant cell lines. DCC-3084 was demonstrated to be CNS penetrable and exhibited dose dependent oral exposure with robust inhibition of the RAS/MAPK pathway in PK/PD models. DCC-3084 accumulated in tumor tissue relative to plasma, further demonstrating a favorable pharmaceutical profile. Oral treatment of DCC-3084 as a single agent resulted in tumor regression in BRAF mutant and KRAS Q61K mutant mouse xenograft models and tumor growth inhibition in KRAS G12C/D mutant models. Additionally, DCC-3084 in combination with a MEKi resulted in tumor regression in KRAS mutant models. Conclusions: The Switch Control inhibitor DCC-3084 broadly inhibits Class I, II and III BRAF mutations, BRAF fusions, and BRAF/CRAF heterodimers leading to tumor regression in preclinical models. The overall preclinical profile of DCC-3084 supports IND-enabling activities towards clinical development in a key area of unmet medical need in RAS and RAF mutant cancers.

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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
DCC-3084 DCC-3084 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
DCC-3084 DCC 3084|DCC3084 BRAF Inhibitor 25 CRAF Inhibitor 12 DCC-3084 is a switch control inhibitor targeting class 1, 2, and 3 BRAF mutations, fusions, and BRAF/CRAF heterodimers, which potentially inhibits Mapk signaling, proliferation, and tumor growth (Cancer Res (2023) 83 (7_Supplement): 4045).
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 fusion Advanced Solid Tumor predicted - sensitive DCC-3084 Preclinical - Cell culture Actionable In a preclinical study, DCC-3084 inhibited downstream signaling and proliferation in cells expressing a BRAF fusion in culture (Cancer Res (2023) 83 (7_Supplement): 4045). detail...
BRAF class 1 Advanced Solid Tumor predicted - sensitive DCC-3084 Preclinical - Cell culture Actionable In a preclinical study, DCC-3084 inhibited downstream signaling and proliferation in cells expressing a BRAF class 1 mutation in culture (Cancer Res (2023) 83 (7_Supplement): 4045). detail...
BRAF class 2 Advanced Solid Tumor predicted - sensitive DCC-3084 Preclinical - Cell culture Actionable In a preclinical study, DCC-3084 inhibited downstream signaling and proliferation in cells expressing a BRAF class 2 mutation in culture (Cancer Res (2023) 83 (7_Supplement): 4045). detail...
BRAF class 3 Advanced Solid Tumor predicted - sensitive DCC-3084 Preclinical - Cell culture Actionable In a preclinical study, DCC-3084 inhibited downstream signaling and proliferation in cells expressing a BRAF class 3 mutation in culture (Cancer Res (2023) 83 (7_Supplement): 4045). detail...