WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206207
CAS#: 1223403-58-4 (free base)
Description: Larotrectinib, also known as ARRY-470 and LOXO-101, is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models. The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons.
MedKoo Cat#: 206207
Name: Larotrectinib free base
CAS#: 1223403-58-4 (free base)
Chemical Formula: C21H22F2N6O2
Exact Mass: 428.17723
Molecular Weight: 428.44
Elemental Analysis: C, 58.87; H, 5.18; F, 8.87; N, 19.62; O, 7.47
Synonym: LOXO 101; LOXO-101; LOXO101; ARRY-470; ARRY470; ARRY 470; Larotrectinib; Vitrakvi.
IUPAC/Chemical Name: (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
InChi Key: NYNZQNWKBKUAII-KBXCAEBGSA-N
InChi Code: InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
SMILES Code: O=C(N1CC[C@@H](C1)O)NC2=C3N=C(N4CCC[C@@H]4C5=CC(F)=CC=C5F)C=CN3N=C2
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:||Larotrectinib (LOXO-101) is an ATP-competitive, selective inhibitor of the tropomyosin-related kinase (TRK) family receptors, with low nanomolar 50% inhibitory concentrations against all three isoforms (TRKA, B, and C).|
|In vitro activity:||To demonstrate activity of Larotrectinib (LOXO-101) in pre-clinical models harboring different variants of TRK oncogenes proliferation assays were performed in three cell line models harboring TRK gene fusions: CUTO-3.29 is derived from a patient with lung adenocarcinoma harboring the MPRIP-NTRK1 gene fusion, the KM12 cell line is a colorectal cancer cell line harboring the TPM3-NTRK1 fusion, and the MO-91 cell line is derived from an acute myeloid leukemia patient harboring the ETV6-NTRK3 fusion. Measurement of proliferation following treatment with LOXO-101 demonstrated a dose-dependent inhibition of cell proliferation in all three cell lines (Fig. 1A–C). The IC50 was less than 100 nM for CUTO-3.29 (Fig. 1A) and less than 10nM for KM12 (Fig. 1B) and MO-91 (Fig. 1C) consistent with the known potency of this drug for the TRK kinase family. Consistent with the inhibition of cellular proliferation, we also observed inhibition of phosphorylation of the MPRIP-TRKA oncoprotein and ERK1/2 in CUTO-3.29 (Fig. 1D), inhibition of TPM3-TRKA, pAKT and pERK1/2 in KM12 (Fig. 1E), and the TEL-TRKC oncoprotein (encoded by ETV6-NTRK3), pAKT and pERK1/2 in MO-91 cells using low doses of LOXO-101 (Fig. 1F). pAKT was not inhibited in the CUTO-3.29 cells by LOXO-101 suggesting that TRK signaling is not AKT-dependent in this tumor. Reference: Cancer Discov. 2015 Oct;5(10):1049-57. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26216294/|
|In vivo activity:||It was determined next whether Larotrectinib (LOXO-101) could inhibit tumor growth in vivo. Athymic nude mice injected with KM12 cells were treated with LOXO-101 orally daily for 2 weeks (Fig. 1G). Dose-dependent tumor inhibition was observed demonstrating the ability of this selective compound to inhibit tumor growth in vivo. Together, these and previously published results indicate that TRK fusions are constitutively activated, regulate critical downstream signaling pathways such as MAPK and AKT, and are inhibited by a highly-specific TRK inhibitor. Reference: Cancer Discov. 2015 Oct;5(10):1049-57. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26216294/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 428.44 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.
|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|
|In vitro protocol:||1. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57. doi: 10.1158/2159-8290.CD-15-0443. Epub 2015 Jul 27. PMID: 26216294; PMCID: PMC4635026. 2. Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies KD, Aisner DL, Pilling AB, Berge EM, Kim J, Sasaki H, Park S, Kryukov G, Garraway LA, Hammerman PS, Haas J, Andrews SW, Lipson D, Stephens PJ, Miller VA, Varella-Garcia M, Jänne PA, Doebele RC. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013 Nov;19(11):1469-1472. doi: 10.1038/nm.3352. Epub 2013 Oct 27. PMID: 24162815; PMCID: PMC3823836.|
|In vivo protocol:||1. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57. doi: 10.1158/2159-8290.CD-15-0443. Epub 2015 Jul 27. PMID: 26216294; PMCID: PMC4635026.|
1: Attia MH, Elrazaz EZ, El-Emam SZ, Taher AT, Abdel-Aziz HA, Abouzid KAM. Synthesis and in-vitro anti-proliferative evaluation of some pyrazolo[1,5-a]pyrimidines as novel larotrectinib analogs. Bioorg Chem. 2019 Nov 21:103458. doi: 10.1016/j.bioorg.2019.103458. [Epub ahead of print] PubMed PMID: 31785854.
2: Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Müller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov 1;30(Supplement_8):viii31-viii35. doi: 10.1093/annonc/mdz382. PubMed PMID: 31738425; PubMed Central PMCID: PMC6859811.
3: Schewe DM, Lenk L, Vogiatzi F, Winterberg D, Rademacher AV, Buchmann S, Henry D, Bergmann AK, Cario G, Cox MC. Larotrectinib in TRK fusion-positive pediatric B-cell acute lymphoblastic leukemia. Blood Adv. 2019 Nov 26;3(22):3499-3502. doi: 10.1182/bloodadvances.2019000700. PubMed PMID: 31725893; PubMed Central PMCID: PMC6880891.
4: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548088/ PubMed PMID: 31643418.
5: Kato S, Fujimura J, Nozaki Y, Yamaguchi S, Takagi T, Hayashi T, Saito T, Henry D, Ku N, Suehara Y. [A Case of Pediatric Soft Tissue Sarcoma with LMNA-NTRK1 Gene Fusion Treated with Larotrectinib under Single Patient Expanded Access System]. Gan To Kagaku Ryoho. 2019 Oct;46(10):1595-1597. Japanese. PubMed PMID: 31631147.
6: Walter AW, Kandula VVR, Shah N. Larotrectinib imaging response in low-grade glioma. Pediatr Blood Cancer. 2020 Jan;67(1):e28002. doi: 10.1002/pbc.28002. Epub 2019 Sep 22. PubMed PMID: 31544356.
7: Federman N, McDermott R. Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer. Expert Rev Clin Pharmacol. 2019 Oct;12(10):931-939. doi: 10.1080/17512433.2019.1661775. Epub 2019 Sep 10. Review. PubMed PMID: 31469968.
8: Ricciuti B, Genova C, Crinò L, Libra M, Leonardi GC. Antitumor activity of larotrectinib in tumors harboring NTRK gene fusions: a short review on the current evidence. Onco Targets Ther. 2019 Apr 30;12:3171-3179. doi: 10.2147/OTT.S177051. eCollection 2019. PubMed PMID: 31118670; PubMed Central PMCID: PMC6503327.
9: Wells AE, Mallen AM, Bui MM, Reed DR, Apte SM. NTRK-1 fusion in endocervical fibroblastic malignant peripheral nerve sheath tumor marking eligibility for larotrectinib therapy: A case report. Gynecol Oncol Rep. 2019 Apr 23;28:141-144. doi: 10.1016/j.gore.2019.04.006. eCollection 2019 May. PubMed PMID: 31080864; PubMed Central PMCID: PMC6506462.
10: Wilson FH, Herbst RS. Larotrectinib in NTRK-Rearranged Solid Tumors(Published as part of the Biochemistry series "Biochemistry to Bedside"). Biochemistry. 2019 Mar 26;58(12):1555-1557. doi: 10.1021/acs.biochem.9b00126. Epub 2019 Mar 13. PubMed PMID: 30865435.
11: Bhangoo MS, Sigal D. TRK Inhibitors: Clinical Development of Larotrectinib. Curr Oncol Rep. 2019 Feb 4;21(2):14. doi: 10.1007/s11912-019-0761-y. Review. PubMed PMID: 30715603.
12: Scott LJ. Larotrectinib: First Global Approval. Drugs. 2019 Feb;79(2):201-206. doi: 10.1007/s40265-018-1044-x. Review. PubMed PMID: 30635837.
13: Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539. PubMed PMID: 30624546; PubMed Central PMCID: PMC6386027.
14: Larotrectinib OK'd for Cancers with TRK Fusions. Cancer Discov. 2019 Jan;9(1):8-9. doi: 10.1158/2159-8290.CD-NB2018-163. Epub 2018 Dec 3. PubMed PMID: 30510115.
15: Sparidans RW, Wang Y, Schinkel AH, Schellens JHM, Beijnen JH. Quantitative bioanalytical assay for the tropomyosin receptor kinase inhibitor larotrectinib in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Dec 1;1102-1103:167-172. doi: 10.1016/j.jchromb.2018.10.023. Epub 2018 Oct 30. PubMed PMID: 30396050.
16: Laetsch TW, Hawkins DS. Larotrectinib for the treatment of TRK fusion solid tumors. Expert Rev Anticancer Ther. 2019 Jan;19(1):1-10. doi: 10.1080/14737140.2019.1538796. Epub 2018 Oct 24. PubMed PMID: 30350734.
17: Ziegler DS, Wong M, Mayoh C, Kumar A, Tsoli M, Mould E, Tyrrell V, Khuong-Quang DA, Pinese M, Gayevskiy V, Cohn RJ, Lau LMS, Reynolds M, Cox MC, Gifford A, Rodriguez M, Cowley MJ, Ekert PG, Marshall GM, Haber M. Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma. Br J Cancer. 2018 Sep;119(6):693-696. doi: 10.1038/s41416-018-0251-2. Epub 2018 Sep 17. PubMed PMID: 30220707; PubMed Central PMCID: PMC6173734.
18: DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, Anderson ME, Davis JL, Qamoos HE, Reynolds ME, Cruickshank S, Cox MC, Hawkins DS, Mascarenhas L, Pappo AS. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018 Nov 1;124(21):4241-4247. doi: 10.1002/cncr.31701. Epub 2018 Sep 11. PubMed PMID: 30204247; PubMed Central PMCID: PMC6263791.
19: Berger S, Martens UM, Bochum S. Larotrectinib (LOXO-101). Recent Results Cancer Res. 2018;211:141-151. doi: 10.1007/978-3-319-91442-8_10. Review. PubMed PMID: 30069765.
20: Halalsheh H, McCarville MB, Neel M, Reynolds M, Cox MC, Pappo AS. Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma. Pediatr Blood Cancer. 2018 Oct;65(10):e27271. doi: 10.1002/pbc.27271. Epub 2018 Jun 12. PubMed PMID: 29893456.
Larotrectinib (LOXO-101, ARRY-470) is an FDA-approved drug for the treatment of cancer. It is an inhibitor of tropomyosin kinase receptors TrkA, TrkB, and TrkC. It was discovered by Array BioPharma and licensed to Loxo Oncology in 2013.
On 26 November 2018, Larotrectinib was approved by the FDA, after having been initially awarded orphan drug status in 2015 for soft tissue sarcoma and breakthrough therapy designation in 2016 for the treatment of metastatic solid tumors with NTRK fusion.. The approval was unusual in that it was only the second agent approved not for use with cancers of specific tissues, but rather for any tissue carrying specific mutations (i.e. the approval is "tissue agnostic").
Copied from https://en.wikipedia.org/wiki/Larotrectinib