LOXO-101

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

LOXO-101（ARRY-470，Larotrectinib）是一种有效的选择性泛 TRK 抑制剂，针对 TRKA、TRKB 和 TRKC 激酶的细胞 IC50 为 2-20 nM。

LOXO-101 (ARRY-470, Larotrectinib) is potent, selective pan-TRK inhibitor with cellular IC50 of 2-20 nM against TRKA, TRKB, and TRKC kinases; demonstrates excellent selectivity against a panel of 226 non-TRK kinases with one exception (TNK2 IC50=576 nM); inhibits fusion oncoprotein and cellular proliferation in TRK-fusion-bearing human-derived cancer cell lines; markedly attenuates bone cancer pain and significantly blocks the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone; inhibits tumor growth in vivo in TRK fusion-positive cancer models.Blood Cancer Phase 2 Clinical(In Vitro):Larotrectinib (LOXO-101) is an ATP-competitive oral inhibitor of the tropomyosin-related kinase (TRK) family of receptor kinases (TRKA, B, and C), with low nanomolar 50% inhibitory concentrations against all three isoforms, and 1,000-fold or greater selectivity relative to other kinases. Measurement of proliferation following treatment with Larotrectinib (LOXO-101) demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91 consistent with the known potency of this drug for the TRK kinase family. (In Vivo):In rat and monkey studies, Larotrectinib (LOXO-101) demonstrates 33-100% oral bioavailability and 60-65% plasma protein binding. It has low brain penetration, and is well tolerated in 28 day (d) GLP toxicology studies. A single dose (30 mg/kg) of Larotrectinib (LOXO-101) reduces tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in the tumor >80%. Athymic nude mice injected with KM12 cells are treated with Larotrectinib (LOXO-101) orally daily for 2 weeks. Dose-dependent tumor inhibition is observed demonstrating the ability of this selective compound to inhibit tumor growth in vivo. Larotrectinib (LOXO-101) (200mg/kg/day p.o for six weeks) reduces leukemic infiltration to undetectable levels in the bone marrow and spleen compared to vehicle-treated mice. Mice treated with Larotrectinib (LOXO-101) are still alive and leukemia-free four weeks after the cessation of treatment, as determined by Xenogen imaging.

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ARRY470 | ARRY-470 | ARRY 470 | LOXO 101 | LOXO101 | Larotrectinib

Tyrosine Kinase

Trk Receptor

Trk Receptor

Cancer

Blood cancer

1223403-58-4

428.4352

C21H22F2N6O2

>98% (HPLC)

DMSO: ≥ 4.6 mg/mL

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F

1-Pyrrolidinecarboxamide, N-[5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxy-, (3S)-

(-20℃)

With Ice Pack

≥ 2 years