Pralsetinib (BLU-667)

Blu667 is a highly potent and selective RET inhibitor with an IC50 of 0.4 nM for wild type RET kinase.

Signaling Pathways >> Others >> Others

Research Areas >> Cancer

IC50: 0.12 nM (Wild type RET)[2]

Blu667 is a RET inhibitor extracted from patent US20170121312A1, compound example 129[1]. BLU-667 demonstrates more than 10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. BLU-667 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. BLU-667 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)[2].

BLU-667 potently inhibits growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). BLU667 showed potent 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[2].

KIF5B-RET Ba/F3 cells are exposed to compound concentrations ranging from 25 µM to 95.4 pM for 48 hours, and proliferation is assessed with Cell Titer Glo. TT, MZ-CRC-1, TPC-1 or LC2/ad cells are exposed to compound for 4 days and proliferation is measured by BrdU incorporation[2].

Mice[2] BALB/c nude mice are inoculated subcutaneously into the right flank with KIF5B-RET Ba/F3 cells, KIF5B-RET V804L Ba/F3 cells, or TT cells. For all experiments, mice are dosed twice-daily with vehicle, 3 mg/kg, 10 mg/kg, or 30 mg/kg BLU-667 or once-daily with 60 mg/kg BLU-667 or 60 mg/kg cabozantinib[2].

[1]. Brumaker J, et al. Inhibitors of ret. US20170121312A1.

[2]. Subbiah V, et al. Precision Targeted Therapy With BLU-667 for RET-Driven Cancers. American Association for Cancer Research. 10.1158/2159-8290.CD-18-0338.

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