Pralsetinib (Blu667) (BLU-667) is a highly potent, selective RET inhibitor (IC50s: 0.4, 0.3, 0.4, 0.4, and 0.4 nM for WT RET, RET mutants V804L, V804M, M918T and CCDC6-RET fusion).

RET (V804M):0.4 nM, RET (V804L):0.3 nM, RET (WT):0.4 nM, CCDC6-RET:0.4 nM, RET (M918T):0.4 nM

Pralsetinib demonstrates more than 10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. Pralsetinib demonstrates potent activity (IC50: 0.4 nM) against common oncogenic RET alterations, including RET M918T, an activating mutation found in MTC, as well as the CCDC6-RET fusion observed in PTC and NSCLC. Pralsetinib suppresses RET pathway signaling in a panel of RET-driven cell lines: LC2/ad (CCDC6-RET, NSCLC), MZ-CRC-1 (RET M918T, MTC), and TT (RET C634W, MTC).

Pralsetinib potently inhibits the growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR-2. Pralsetinib shows dose-dependent activity against both KIF5B-RET Ba/F3 and KIF5B-RET V804L Ba/F3 allograft tumors with doses as low as 10 mg/kg twice daily.