Entrectinib

Research use only, not for human use.

Entrectinib (NMS-E628, RXDX-101, NMS-01191372) is a potent, ATP-competitive, orally available pan-TRK, ROS1 and ALK inhibitor with IC50 of 1/3/5/12/7 nM for TRKA/TRKB/TRKC/ALK/ROS1, respectively.

Entrectinib (NMS-E628, RXDX-101, NMS-01191372) is a potent, ATP-competitive, orally available pan-TRK, ROS1 and ALK inhibitor with IC50 of 1/3/5/12/7 nM for TRKA/TRKB/TRKC/ALK/ROS1, respectively; exhibits high antiproliferative activity against colorectal carcinoma cell line KM12 with IC50 of 17 nM, abolishes autophosphorylation of TPM3-TRKA, concomitant with complete inhibition of the phosphorylation of PLCγ1, AKT, and MAPK; induces regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models.Lung Cancer Phase 2 Clinical(In Vitro):Entrectinib (NMS-E628) is found to be exquisitely active in inhibiting the proliferation of a limited number of cell lines: the TRKA-driven colorectal carcinoma cell line KM12 (IC50 of 17 nM), the ALK-dependent ALCL cell lines SU-DHL-1, Karpas-299, SUP-M2 and SR-786 (IC50 of 20, 31, 41, and 81 nM, respectively), the ALK-dependent NSCLC cell line NCI-H2228 (IC50 of 68 nM) and the FLT3-dependent AML cell line MV-4-11 (IC50 of 81 nM). Entrectinib potently blocks proliferation of Ba/F3-TEL-TRKB (IC50 of 2.9 nM), Ba/F3-TEL-TRKC (IC50 of 3.3 nM), and Ba/F3-TEL-ROS1 (IC50 of 5.3 nM) cells, with a high degree of selectivity versus parental Ba/F3 cells or those transformed by nontargeted kinases such as ABL and RET, which are inhibited with IC50s in the range of 2 to 3 μM. Entrectinib significantly inhibits the growth of TrkB-expressing NB cells in vitro, and it significantly enhances the growth inhibition of Irino-TMZ when used in combination.(In Vivo):Oral administration of entrectinib to tumor-bearing mice induces regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Single agent therapy results in significant tumor growth inhibition in animals treated with entrectinib compared to control animals.

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Animal Model:Male C57BL/6 mice (6-8 weeks old, 20-25 g; Bleomycin-induced pulmonary fibrosis model).Dosage:20, 40, 60 mg/kg Administration:Intragastric Administration; single daily for 7 days.Result:Significantly improved lung function in the pulmonary fibrosis model mice.

NMS-E628 | RXDX-101 | NMS-01191372

Tyrosine Kinase

Trk Receptor

ALK|ROS1|TrkA|TrkB|TrkC

Cancer

Lung Cancer

1108743-60-7

560.6375

C31H34F2N6O2

>98% (HPLC)

DMSO: ≥ 31 mg/mL

O=C(NC1=NNC2=C1C=C(CC3=CC(F)=CC(F)=C3)C=C2)C4=CC=C(N5CCN(C)CC5)C=C4NC6CCOCC6

Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-

(-20℃)

With Ice Pack

≥ 2 years