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Entrectinib

Names

[ CAS No. ]:
1108743-60-7

[ Name ]:
Entrectinib

[Synonym ]:
UNII:L5ORF0AN1I
N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide
NMS E628
Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-
RXDX-101
entrectinib
N-[5-(3,5-Difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide
RXDX101
NMS-E628
RXDX 101

Biological Activity

[Description]:

Entrectinib is a potent and orally available Trk, ROS1, and ALK inhibitor; inhibits TrkA, TrkB, TrkC, ROS1 and ALK with IC50 values of 1, 3, 5, 12 and 7 nM, respectively.

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ALK
Signaling Pathways >> Autophagy >> Autophagy
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ROS
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Trk Receptor
Research Areas >> Cancer

[Target]

IC50: 1 nM (TrkA), 1 nM (TrkB), 1 nM (TrkC), 1 nM (ROS1),1 nM (ALK)[1]


[In Vitro]

Entrectinib 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[1]. 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[2].

[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[1]. Single agent therapy results in significant tumor growth inhibition in animals treated with entrectinib compared to control animals[2].

[Cell Assay]

NLF, NLF-TrkB, SY5Y or SY5Y-TrkB cells are plated in 96 well plates, and they are exposed to drug at different concentrations (1, 5, 10, 20, 30, 50 and 100 nM of entrectinib, 1.5 μM Irino and 50 μM TMZ, respectively) for one hr followed by addition of 100 ng/mL of BDNF. Plates are harvested at 24, 48, and 72 hr following addition of drug. The plates are processed and cell viability is analyzed using a standard SRB assay protocol[2].

[Animal admin]

Mice: Entrectinib is reconstituted in 0.5% methylcellulose containing 1% Tween 80 at a final dosing volume of 10 mL/kg (e.g., 0.2 mL for a 20 gm mouse). Treatment with entrectinib, Irino and TMZ started about 15–17 days after tumor inoculation when the average tumor size is 0.2 cm3. Mice are sacrificed when tumor volume reached 3 cm3. Tumors are harvested and flash frozen on dry ice for analysis of protein expression[2].

[References]

[1]. Ardini E, et al. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39.

[2]. Iyer R, et al. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016 Mar 28;372(2):179-86.


[Related Small Molecules]

Brigatinib | lorlatinib | Alectinib (CH5424802) | LOXO-101 | TAE684(NVP-TAE684) | ANA-12 | LM22B 10 | AZD-3463 | GW441756 | Repotrectinib | Ensartinib | GNF-5837 | AP26113 | K 02288 | ASP3026

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
717.5±60.0 °C at 760 mmHg

[ Molecular Formula ]:
C31H34F2N6O2

[ Molecular Weight ]:
560.638

[ Flash Point ]:
387.7±32.9 °C

[ Exact Mass ]:
560.271118

[ PSA ]:
85.52000

[ LogP ]:
5.66

[ Vapour Pressure ]:
0.0±2.3 mmHg at 25°C

[ Index of Refraction ]:
1.672

[ Storage condition ]:
2-8°C

Related Compounds