FORE8394 was designed to target a wide range of BRAF mutations while sparing wild type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors, but also disrupts constitutively active dimeric BRAF class II mutants, fusions, splice variants and others.
About the program
FORE8394 (formerly PLX-8394) is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. Its inhibition of ERK signaling makes it a strong candidate for the treatment of tumors driven by class I or II BRAF mutations and fusions.
The U.S. Food and Drug Administration (FDA) granted Orphan Drug designation for FORE8394 for the Treatment of Primary Brain and CNS Malignancies and Fast Track designation for the treatment of cancers harboring BRAF Class 1 (V600) and Class 2 (including fusions) alterations who have exhausted prior therapies.
Beyond BRAFV600 mutations
Unlike first-generation RAF inhibitors, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a “paradox breaker,” FORE8394 could therefore treat acquired resistance to current RAF inhibitors, and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors.
As a BRAF-specific dimer breaker, FORE8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants, as well as BRAFV600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling.
PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation
Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer
RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling
RAF inhibitors that evade paradoxical MAPK pathway activation
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas in Vivo and Ex Vivo.
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
Information about our ongoing clinical trial
Fore is running a clinical trial open for patients with advanced cancer with BRAF alterations, including both patients with CNS and solid tumors NCT02428712.