DS-6051b

Taletrectinib (DS-6051b) is a potent, orally active, and new-generation selective ROS1/NTRK inhibitor. Taletrectinib potently inhibits recombinant ROS1, NTRK1, and NTRK3 with IC50s of 0.207, 0.622, 2.28, and 0.98 nM, respectively. Taletrectinib also inhibits ROS1 G2032R and other Crizotinib-resistant ROS1 mutants[1][2].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ROS

The IC50 of Taletrectinib (1-1000 nM; 72 hours) against Ba/F3-TPM3-NTRK1, Ba/F3-ETV6-NTRK1, -NTRK2, -NTRK3, or KM12 cells is ~3-20 nM[1]. Taletrectinib (0.001-1000 nM; 2 hours) dose dependently inhibited autophosphorylation of ROS1 in U-118-MG cells in vitro[1]. Taletrectinib potently inhibits autophosphorylation of ROS1 in JFCR-165, JFCR-168, and MGH193-1B cells[1]. Taletrectinib partially suppresses phospho-NTRK1 at 10 nM, and completely suppresses by 100 nM. Taletrectinib free base potently inhibits recombinant ROS1, NTRK1, and NTRK3 in sub-nanomolar concentration in an ATP-competitive manner. Taletrectinib almost completely inhibits ACK, ALK, DDR1, and LTK at 0.2 μM among 160 kinases in the presence of 1 mM ATP, but did not inhibit other 152 kinases strongly[1]. Taletrectinib effectively inhibits Crizotinib-resistant ROS1 secondary mutations, including G2032R solvent front mutation[1]. Cell Viability Assay[1] Cell Line: TPM3-NTRK1-induced Ba/F3 cells, KM12 cells Concentration: 1-1000 nM Incubation Time: 72 hours Result: Inhibited TPM3-NTRK1-induced Ba/F3 cells and KM12 cells viability. Western Blot Analysis[1] Cell Line: U-118 MG cells (harboring FIG-ROS1 fusion gene) Concentration: 0.001-1000 nM Incubation Time: 2 hours Result: Dose dependently inhibited autophosphorylation of ROS1 in U-118-MG cells.

Taletrectinib (DS-6051b) (25-200 mg/kg; p.o.; once daily for 18 days) shows antitumor activity[1]. Taletrectinib (6.25-200 mg/kg; p.o.; once daily for 8 days) inhibits NTRK-rearranged cancer in Balb-c nu/nu mice bearing KM12 cells[1]. Taletrectinib (3-100 mg/kg; p.o.; once daily for 4 days) shows rapid tumor regression in the wild-type (WT) and the G2032R-mutant Ba/F3-bearing mice without severe body weight loss[1]. Animal Model: Balb-c nu/nu mice (bearing U-118 MG cells)[1] Dosage: 25, 50, 100, and 200 mg/kg Administration: P.o.; once daily for 18 days Result: Effectively inhibited tumor growth at ≥25 mg/kg without significant body weight loss.

[1]. Katayama R, et al. The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat Commun. 2019;10(1):3604. Published 2019 Aug 9.

[2]. Fujiwara Y, et al. Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study. Oncotarget. 2018;9(34):23729-23737. Published 2018 May 4.