Selitrectinib

• CAT Number: I004247
• CAS Number: 2097002-61-2
• Molecular Formula: C20H21FN6O
• Molecular Weight: 380.42
• Purity: ≥95%
• Synonyms: (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22-heptaen-17-one
• InChI: InChI=1S/C20H21FN6O/c1-12-4-5-16-14(9-13(21)10-22-16)17-3-2-7-26(17)18-6-8-27-19(25-18)15(11-23-27)20(28)24-12/h6,8-12,17H,2-5,7H2,1H3,(H,24,28)/t12-,17-/m1/s1
• InChIKey: OEBIHOVSAMBXIB-SJKOYZFVSA-N
• SMILES: CC1CCC2=C(C=C(C=N2)F)C3CCCN3C4=NC5=C(C=NN5C=C4)C(=O)N1

Selitrectinib (LOXO-195) is a next-generation TRK kinase inhibitor, with IC50s of 0.6 nM and <2.5 nM for TRKA and TRKC, respectively[1].
Selitrectinib (LOXO-195) demonstrates strong binding to the wild-type TRKA, TRKB and TRKC kinase domains. Selitrectinib (LOXO-195) has potent (IC50<1 nM) inhibitory activity in kinase enzyme assays. Importantly, Selitrectinib (LOXO-195) achieves low nanomolar inhibitory activity against TRKA G595R, TRKC G623R, and TRKA G667C, with IC50s ranging from 2.0-9.8 nM. 228 individual kinases in vitro are profiled at a Selitrectinib (LOXO-195) concentration of 1 μM, which is ~1667-fold higher than its IC50 for TRKA (0.6 nM). Selitrectinib (LOXO-195) is more than 1000-fold selective for 98% of non-TRK kinases tested. Selitrectinib (LOXO-195) demonstrates potent inhibition of cell proliferation in TRK fusion-containing KM12, CUTO-3, and MO-91 cell lines (IC50≤5 nM)[1].
Stably transfected NIH-3T3 ΔTRKA and ΔTRKA-G595R cells are implanted subcutaneously into the flanks of nude mice. Both larotrectinib and Selitrectinib (LOXO-195) are effective at reducing phosphorylated TRKA in tumors driven by ΔTRKA. In contrast, only Selitrectinib (LOXO-195) strongly suppresses phospho-TRKA in ΔTRKA-G595R cells in a dose-dependent manner. Selitrectinib (LOXO-195) also causes inhibition of tumor growth relative to vehicle at all doses in four TRKA-dependent tumor models (ΔTRKA, ΔTRKA-G595R, ΔTRKAG667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells. Larotrectinib inhibits KM12 and NIH 3T3-ΔTRKA tumors to a similar degree. Group mean body weight loss does not exceed 5% for any agent. Selitrectinib (LOXO-195) displays high selectivity for the TRK proteins[1]

Reference

[1]. Drilon A, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972.
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