Entrectinib
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MedKoo CAT#: 206181

CAS#: 1108743-60-7

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.


Chemical Structure

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Entrectinib
CAS# 1108743-60-7

Theoretical Analysis

MedKoo Cat#: 206181
Name: Entrectinib
CAS#: 1108743-60-7
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

Price and Availability

Size Price Availability Quantity
50.0mg USD 150.0 Same day
100.0mg USD 250.0 Same day
200.0mg USD 450.0 Same day
500.0mg USD 950.0 Same day
1.0g USD 1750.0 Same day
2.0g USD 3250.0 Same day
5.0g USD 5250.0 Same day
10.0g USD 8950.0 2 Weeks
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Synonym: RXDX101; RXDX 101; RXDX-101; NMS E628; NMSE628; NMS-E628; Entrectinib

IUPAC/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 Key: HAYYBYPASCDWEQ-UHFFFAOYSA-N

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)

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

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

Biological target: Entrectinib (NMS-E628) is a CNS-active pan-Trk, ROS1, and ALK inhibitor.
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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.33 89.77
DMF 30.0 53.51
DMF:PBS (pH 7.2) (1:4) 0.2 0.36
Ethanol 50.5 90.08

Preparing Stock Solutions

The following data is based on the product molecular weight 560.64 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Smith KM, Fagan PC, Pomari E, Germano G, Frasson C, Walsh C, Silverman I, Bonvini P, Li G. Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia. Mol Cancer Ther. 2018 Feb;17(2):455-463. doi: 10.1158/1535-7163.MCT-17-0419. Epub 2017 Dec 13. PMID: 29237803. 2. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A. 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. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. PMID: 26939704. 3. Fischer H, Ullah M, de la Cruz CC, Hunsaker T, Senn C, Wirz T, Wagner B, Draganov D, Vazvaei F, Donzelli M, Paehler A, Merchant M, Yu L. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol. 2020 Jun 9;22(6):819-829. doi: 10.1093/neuonc/noaa052. PMID: 32383735; PMCID: PMC7283026. 4. Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, Guan P, Kolla V, Wei G, Cam N, Li G, Hornby Z, Brodeur GM. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016 Mar 28;372(2):179-86. doi: 10.1016/j.canlet.2016.01.018. Epub 2016 Jan 18. PMID: 26797418; PMCID: PMC4792275.
In vitro protocol: 1. Smith KM, Fagan PC, Pomari E, Germano G, Frasson C, Walsh C, Silverman I, Bonvini P, Li G. Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia. Mol Cancer Ther. 2018 Feb;17(2):455-463. doi: 10.1158/1535-7163.MCT-17-0419. Epub 2017 Dec 13. PMID: 29237803. 2. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A. 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. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. PMID: 26939704.
In vivo protocol: 1. Fischer H, Ullah M, de la Cruz CC, Hunsaker T, Senn C, Wirz T, Wagner B, Draganov D, Vazvaei F, Donzelli M, Paehler A, Merchant M, Yu L. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol. 2020 Jun 9;22(6):819-829. doi: 10.1093/neuonc/noaa052. PMID: 32383735; PMCID: PMC7283026. 2. Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, Guan P, Kolla V, Wei G, Cam N, Li G, Hornby Z, Brodeur GM. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016 Mar 28;372(2):179-86. doi: 10.1016/j.canlet.2016.01.018. Epub 2016 Jan 18. PMID: 26797418; PMCID: PMC4792275.

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  1: 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.

2: 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.

3: 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.

4: 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.

5: 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.

6: 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.

7: Wang Q, Fang P, Zheng L, Ye L. Quantification and pharmacokinetic study of entrectinib in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry. Biomed Chromatogr. 2019 Apr;33(4):e4467. doi: 10.1002/bmc.4467. Epub 2019 Jan 7. PubMed PMID: 30549079.

8: Entrectinib Effective across NTRK Fusion-Positive Cancers. Cancer Discov. 2019 Jan;9(1):OF4. doi: 10.1158/2159-8290.CD-NB2018-156. Epub 2018 Nov 27. PubMed PMID: 30482804.

9: Pacenta HL, Macy ME. Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. Review. PubMed PMID: 30425456; PubMed Central PMCID: PMC6204873.

10: Attwa MW, Kadi AA, Alrabiah H, Darwish HW. LC-MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation. J Pharm Biomed Anal. 2018 Oct 25;160:19-30. doi: 10.1016/j.jpba.2018.07.032. Epub 2018 Jul 22. PubMed PMID: 30055343.

11: Liu D, Offin M, Harnicar S, Li BT, Drilon A. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. Review. PubMed PMID: 30050303; PubMed Central PMCID: PMC6055893.

12: Attwa MW, Darwish HW, Alhazmi HA, Kadi AA. Investigation of metabolic degradation of new ALK inhibitor: Entrectinib by LC-MS/MS. Clin Chim Acta. 2018 Oct;485:298-304. doi: 10.1016/j.cca.2018.07.009. Epub 2018 Jul 10. PubMed PMID: 30006284.

13: Nishiyama A, Yamada T, Kita K, Wang R, Arai S, Fukuda K, Tanimoto A, Takeuchi S, Tange S, Tajima A, Furuya N, Kinoshita T, Yano S. Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model. Clin Cancer Res. 2018 May 15;24(10):2357-2369. doi: 10.1158/1078-0432.CCR-17-1623. Epub 2018 Feb 20. PubMed PMID: 29463555.

14: Ambati SR, Slotkin EK, Chow-Maneval E, Basu EM. Entrectinib in Two Pediatric Patients With Inflammatory Myofibroblastic Tumors Harboring ROS1 or ALK Gene Fusions. JCO Precis Oncol. 2018;2018. pii: https://ascopubs.org/doi/10.1200/PO.18.00095. Epub 2018 Sep 13. PubMed PMID: 31763577.

15: Smith KM, Fagan PC, Pomari E, Germano G, Frasson C, Walsh C, Silverman I, Bonvini P, Li G. Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia. Mol Cancer Ther. 2018 Feb;17(2):455-463. doi: 10.1158/1535-7163.MCT-17-0419. Epub 2017 Dec 13. PubMed PMID: 29237803.

16: Sigal D, Tartar M, Xavier M, Bao F, Foley P, Luo D, Christiansen J, Hornby Z, Maneval EC, Multani P. Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer. J Natl Compr Canc Netw. 2017 Nov;15(11):1317-1322. doi: 10.6004/jnccn.2017.7029. PubMed PMID: 29118225.

17: Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017 Apr;7(4):400-409. doi: 10.1158/2159-8290.CD-16-1237. Epub 2017 Feb 9. PubMed PMID: 28183697; PubMed Central PMCID: PMC5380583.

18: 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. 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. 2016 Apr 14;59(7):3392-408. doi: 10.1021/acs.jmedchem.6b00064. Epub 2016 Mar 30. Erratum in: J Med Chem. 2019 Sep 12;62(17):8364. PubMed PMID: 27003761.

19: Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A. 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. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. PubMed PMID: 26939704.

20: Drilon A, Li G, Dogan S, Gounder M, Shen R, Arcila M, Wang L, Hyman DM, Hechtman J, Wei G, Cam NR, Christiansen J, Luo D, Maneval EC, Bauer T, Patel M, Liu SV, Ou SH, Farago A, Shaw A, Shoemaker RF, Lim J, Hornby Z, Multani P, Ladanyi M, Berger M, Katabi N, Ghossein R, Ho AL. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol. 2016 May;27(5):920-6. doi: 10.1093/annonc/mdw042. Epub 2016 Feb 15. PubMed PMID: 26884591; PubMed Central PMCID: PMC4843186.



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