NRX-0305 is an orally bioavailable, pan-mutant BRAF degrader that exhibits single-agent and combination efficacy with MEKi or anti-EGFR across Class 1/2/3 BRAF-mutant cancers

Activating mutations in BRAF, a central kinase within the MAPK pathway, promote sustained pathway signaling and drive oncogenic transformation across multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). BRAF mutations are categorized into three functional classes: Class 1 (e.g., V600X), which are RAS-independent and targetable with approved BRAF inhibitors; Class 2, which signal as constitutive dimers; and Class 3, which are kinase-impaired and depend on upstream RAS activation. While approved BRAF inhibitors provide significant survival benefit to patients with Class 1 mutations, they are ineffective against tumors harboring Class 2 or 3 mutations, which remain refractory to current BRAF-targeted therapies. Motivated by the lack of therapeutic options for patients with Class 2 and 3 BRAF mutations, we developed NRX-0305, a potent and orally bioavailable pan-mutant BRAF degrader that selectively eliminates mutant BRAF while sparing the wild-type protein. In vitro, NRX-0305 potently degraded Class 1/2/3 mutant BRAF and suppressed downstream pERK1/2 signaling, resulting in strong antiproliferative effects across a diverse panel of Class 1/2/3 BRAF-mutant cell lines, including those expressing BRAF fusion proteins. In vivo, daily oral administration of NRX-0305 induced robust, dose-dependent BRAF degradation and pathway inhibition, producing marked single-agent efficacy in multiple Class 1/2/3 cell lines-derived xenograft and patient-derived xenograft models. Furthermore, combination studies of NRX-0305 with MEK inhibitor or anti-EGFR demonstrated enhanced antitumor activity, supporting its potential use in clinically relevant combination regimens. Collectively, these studies demonstrate NRX-0305 is a potent, mutant-selective BRAF degrader that can overcome the limitations of approved BRAF inhibitors, offering broad therapeutic potential both as a single agent and in combination with MEKi or anti-EGFR antibodies across Class 1/2/3 BRAF-mutant cancers.