Entrectinib, also known as RXDX-101 and NMS-E628, is an oral small molecule inhibitor of TrkA, TrkB and TrkC, as well as ROS1 and ALK, with high potency and selectivity. RXDX-101 has demonstrated potent pharmacological activity in preclinical studies and has the potential to be first-in-class against the Trk family of kinases. PXDX-101 has been well tolerated in patients with advanced solid tumors. PXDX-101 is currently in clinical trials, and is being developed by Ignyta.
Chemical Formula: C31H34F2N6O2
Exact Mass: 560.27113
Molecular Weight: 560.64
Elemental Analysis: C, 66.41; H, 6.11; F, 6.78; N, 14.99; O, 5.71
Chemical Name: N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide
InChi Code: InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
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
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.
Facchinetti F, Friboulet L. Profile of entrectinib and its potential in the treatment of ROS1-positive NSCLC: evidence to date. Lung Cancer (Auckl). 2019 Sep 9;10:87-94. doi: 10.2147/LCTT.S190786. eCollection 2019. PubMed PMID: 31572036; PubMed Central PMCID: PMC6747675.
Entrectinib OK'd for Cancers with NTRK Fusions, NSCLC. Cancer Discov. 2019 Oct;9(10):OF2. doi: 10.1158/2159-8290.CD-NB2019-101. Epub 2019 Aug 30. PubMed PMID: 31471291.
Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, Buffa L, Canevari G, Ceriani L, Colombo M, Corti L, Donati D, Fasolini M, Felder E, Fiorelli C, Fiorentini F, Galvani A, Isacchi A, Borgia AL, Marchionni C, Nesi M, Orrenius C, Panzeri A, Pesenti E, Rusconi L, Saccardo MB, Vanotti E, Perrone E, Orsini P. Correction to Discovery of Entrectinib: A New 3-Aminoindazole as a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor. J Med Chem. 2019 Sep 12;62(17):8364. doi: 10.1021/acs.jmedchem.9b01259. Epub 2019 Aug 19. PubMed PMID: 31424209.
Al-Salama ZT, Keam SJ. Entrectinib: First Global Approval. Drugs. 2019 Sep;79(13):1477-1483. doi: 10.1007/s40265-019-01177-y. Review. PubMed PMID: 31372957.
Ku BM, Bae YH, Lee KY, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. Entrectinib resistance mechanisms in ROS1-rearranged non-small cell lung cancer. Invest New Drugs. 2019 May 24. doi: 10.1007/s10637-019-00795-3. [Epub ahead of print] PubMed PMID: 31124056.
Entrectinib Shows Pediatric Potential. Cancer Discov. 2019 Jul;9(7):OF4. doi: 10.1158/2159-8290.CD-NB2019-060. Epub 2019 May 21. PubMed PMID: 31113803.
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