Catalog Number
ACM1108743607
Description
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.
Synonyms
RXDX101; RXDX 101; RXDX-101; NMS E628; NMSE628; NMS-E628; Entrectinib
IUPAC Name
N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide
Molecular Formula
C31H34F2N6O2
Canonical SMILES
O=C(NC1=NNC2=C1C=C(CC3=CC(F)=CC(F)=C3)C=C2)C4=CC=C(N5CCN(C)CC5)C=C4NC6CCOCC6
InChI
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)
InChI Key
HAYYBYPASCDWEQ-UHFFFAOYSA-N
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Storage
Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
Biological Target
Entrectinib (NMS-E628) is a CNS-active pan-Trk, ROS1, and ALK inhibitor.
Drug Formulation
This drug may be formulated in DMSO
Elemental Analysis
C, 66.41; H, 6.11; F, 6.78; N, 14.99; O, 5.71
HS Tariff Code
2934.99.9001
In Vitro Activity
Entrectinib treatment potently blocked cellular proliferation in NTRK fusion-positive AML patient-derived cell lines (Fig. 1C) and resulted in rapid apoptotic cell death in a dose- and time-dependent manner (Fig. 2). Cell death was preceded by rapid reduction in TRK autophosphorylation at Y764/Y765 in the kinase activation loop and Y785, the PLCγ interaction site, and by reduced phosphorylation of downstream signaling partners, PLCγ, ERK, and STAT3 (Fig. 1E and F). TRK kinase inhibition was also accompanied by a reduction in ETV6-TRKC fusion protein levels (Fig. 1F). Similar reductions in PML-RARA fusion protein stability after retinoic acid/arsenic trioxide treatment or estrogen receptor after fulvestrant treatment have been described. Altered protein stability upon entrectinib treatment may be a novel mechanism of action against TRKC fusion proteins as reduced TRK fusion protein levels have not been seen after entrectinib treatment of patient-derived cell lines carrying TRKA fusions or Ba/F3 cells expressing ETV6-NTRK1.
Reference: Mol Cancer Ther. 2018 Feb;17(2):455-463. https://mct.aacrjournals.org/content/17/2/455.long
In Vivo Activity
Significant tumor growth inhibition was observed with entrectinib treatment compared to vehicle (p<0.0001, Fig. 3A). Entrectinib treated mice also demonstrated a significantly prolonged EFS (p<0.0001, Fig. 3B). Analysis of the tumors harvested at different time points after treatment (1, 4 and 6 hr, respectively) showed inhibition of TrkB phosphorylation in tumors treated with entrectinib compared to vehicle controls. Inhibition of phosphorylation was also seen for p-PLCγ, p-Akt and p-Erk in entrectinib treated tumors (Fig. 3C). Densitometric analysis of Western blot images was also performed to indicate the statistical significance of phosphoprotein expression in xenografts upon entrectinib treatment (Fig. S2). Actin levels were unchanged indicating that there is no global inhibition of protein. These results show that entrectinib significantly inhibited the growth of SY5Y-TrkB xenograft as well as Trk phosphorylation in vivo.
Reference: Cancer Lett. 2016 Mar 28; 372(2): 179-186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792275/
Shipping
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.
Stock Solution Storage
0-4 °C for short term (days to weeks), or -20 °C for long term (months).
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