Tucatinib
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MedKoo CAT#: 200291

CAS#: 937263-43-9

Description: Tucatinib, also known as Irbinitinib, ARRY-380 and ONT-380, is a n orally bioavailable inhibitor of the human epidermal growth factor receptor tyrosine kinase ErbB-2 (also called HER2) with potential antineoplastic activity. ErbB-2 inhibitor ARRY-380 selectively binds to and inhibits the phosphorylation of ErbB-2, which may prevent the activation of ErbB-2 signal transduction pathways, resulting in growth inhibition and death of ErbB-2-expressing tumor cells. ErbB-2 is overexpressed in a variety of cancers and plays an important role in cellular proliferation and differentiation.


Chemical Structure

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Tucatinib
CAS# 937263-43-9

Theoretical Analysis

MedKoo Cat#: 200291
Name: Tucatinib
CAS#: 937263-43-9
Chemical Formula: C26H24N8O2
Exact Mass: 480.2022
Molecular Weight: 480.53
Elemental Analysis: C, 64.99; H, 5.03; N, 23.32; O, 6.66

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5450.0 Ready to ship
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Related CAS #: 937263-43-9   937265-83-3 (ARRY-380 analog)  

Synonym: ARRY380; ARRY 380; ARRY-380; ONT380; ONT 380; ONT-380. Irbinitinib; Tucatinib.

IUPAC/Chemical Name: N6-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-((1,2,4)triazolo(1,5-a)pyridin-7-yloxy)phenyl)quinazoline-4,6-diamine

InChi Key: SDEAXTCZPQIFQM-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H24N8O2/c1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)

SMILES Code: CC1=CC(NC2=C3C=C(NC4=NC(C)(C)CO4)C=CC3=NC=N2)=CC=C1OC5=CC6=NC=NN6C=C5

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: HER2 inhibitor with an IC50 of 8 nM
In vitro activity: To investigate the effects of tucatinib on leukemia cells, MTT assays were subsequently performed to determine the cytotoxicity of tucatinib on 2 leukemia cell lines. As shown in Fig. 1B and C, >80% of the HL60/ABCG2 and K562/ABCG2 ABCG2-overexpressing cell lines, and their parental cell lines, HL60 and K562, survived 0.4 µM tucatinib treatment. Therefore, 0.4 µM tucatinib was selected as the maximum working concentration for further experiments. Subsequently, whether tucatinib, at various concentrations, could increase the sensitivity of ABCG2-overexpressing leukemia drug resistant cells to mitoxantrone and topotecan was investigated. As shown in Tables I and andII,II, the ABCG2-overexpressing HL60/ABCG2 and K562/ABCG2 cell lines showed higher IC50 values to the ABCG2 substrates, mitoxantrone and topotecan compared with that in their parental cell lines, respectively. In the presence of 0.1 and 0.2 µM tucatinib, there was a significant increase in sensitivity of the cell lines to the two drugs. Tucatinib (0.4 µM) further increased the sensitivity of leukemia cells to the two drugs in both the ABCG2-overexpressing HL60/ABCG2 and K562/ABCG2 cell lines, and its efficacy was comparable to that of the known ABCG2 inhibitor, FTC (2.5 µM). Conversely, tucatinib did not significantly alter the IC50 value of cisplatin in all the leukemia cell lines, which is a non-ABCG2 substrate. Taken together, these results suggested that tucatinib may significantly sensitize ABCG2-overexpressing leukemia cells to become anti-neoplastic. Reference: Oncol Rep. 2021 Mar; 45(3): 1142–1152. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859976/
In vivo activity: The ability of tucatinib to prevent tumor cell growth in vivo was investigated in HER2+ breast and gastric cancer CDX xenograft models. Female immunocompromised mice implanted with BT-474 cells were treated with tucatinib and evaluated for response. Mice treated with tucatinib exhibited tumor growth delay at doses of 25 or 50 mg/kg tucatinib administered orally every day. This effect was similar to mice treated with trastuzumab monotherapy (Fig. 4A). In contrast, mean tumor volume (MTV) increased > 4-fold in mice treated with vehicle (Fig. 4A). Reference: Mol Cancer Ther. 2020 Apr;19(4):976-987. https://mct.aacrjournals.org/content/19/4/976.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 1.0 2.08
DMSO 49.0 101.97
DMSO:PBS (pH 7.2) (1:2) 0.33 0.69

Preparing Stock Solutions

The following data is based on the product molecular weight 480.53 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. Jing W, Zhou M, Chen R, Ye X, Li W, Su X, Luo J, Wang Z, Peng S. In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells. Oncol Rep. 2021 Mar;45(3):1142-1152. doi: 10.3892/or.2020.7915. Epub 2020 Dec 30. PMID: 33650639; PMCID: PMC7859976. 2. Kulukian A, Lee P, Taylor J, Rosler R, de Vries P, Watson D, Forero-Torres A, Peterson S. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020 Apr;19(4):976-987. doi: 10.1158/1535-7163.MCT-19-0873. PMID: 32241871.
In vitro protocol: 1. Jing W, Zhou M, Chen R, Ye X, Li W, Su X, Luo J, Wang Z, Peng S. In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells. Oncol Rep. 2021 Mar;45(3):1142-1152. doi: 10.3892/or.2020.7915. Epub 2020 Dec 30. PMID: 33650639; PMCID: PMC7859976.
In vivo protocol: 1. Kulukian A, Lee P, Taylor J, Rosler R, de Vries P, Watson D, Forero-Torres A, Peterson S. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020 Apr;19(4):976-987. doi: 10.1158/1535-7163.MCT-19-0873. PMID: 32241871.

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This product was cited in below publication 1. Conlon NT, Kooijman JJ, van Gerwen SJC, Mulder WR, Zaman GJR, Diala I, Eli LD, Lalani AS, Crown J, Collins DM. Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors. Br J Cancer. 2021 Jan 21. doi: 10.1038/s41416-020-01257-x. Epub ahead of print. PMID: 33473169. 2. Conlon NT, Kooijman JJ, van Gerwen SJC, Mulder WR, Zaman GJR, Diala I, Eli LD, Lalani AS, Crown J, Collins DM. Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors. Br J Cancer. 2021 Mar;124(7):1249-1259. doi: 10.1038/s41416-020-01257-x. Epub 2021 Jan 21. PMID: 33473169; PMCID: PMC8007737.

1: Sun H, Cardinal KA, Wienkers L, Chin A, Kumar V, Neace C, Henderson C, Endres CJ, Topletz-Erickson A, Regal K, Vo A, Alley SC, Lee AJ. Elimination of tucatinib, a small molecule kinase inhibitor of HER2, is primarily governed by CYP2C8 enantioselective oxidation of gem-dimethyl. Cancer Chemother Pharmacol. 2022 Apr 18. doi: 10.1007/s00280-022-04429-z. Epub ahead of print. PMID: 35435471.

2: O'Brien NA, Huang HKT, McDermott MSJ, Madrid AM, Luo T, Ayala R, Issakhanian S, Gong KW, Lu M, Zhang J, Slamon DJ. Tucatinib has Selective Activity in HER2-Positive Cancers and Significant Combined Activity with Approved and Novel Breast Cancer-Targeted Therapies. Mol Cancer Ther. 2022 Apr 13:OF1-OF11. doi: 10.1158/1535-7163.MCT-21-0847. Epub ahead of print. PMID: 35417017.

3: Yan F, Rinn KJ, Kullnat JA, Wu AY, Ennett MD, Scott EL, Kaplan HG. Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report. J Natl Compr Canc Netw. 2022 Apr 11:1-8. doi: 10.6004/jnccn.2022.7006. Epub ahead of print. PMID: 35405660.

4: Zhang Y, Liu YN, Xie S, Xu X, Xu RA. Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC-MS/MS assay. Pharm Biol. 2022 Dec;60(1):621-626. doi: 10.1080/13880209.2022.2048862. PMID: 35289238; PMCID: PMC8928849.

5: Ahn D, Walden D, Bekaii-Saab T. Tucatinib: an investigational novel therapeutic agent for the treatment of HER-2 colorectal cancer. Expert Opin Investig Drugs. 2022 Mar 17:1-5. doi: 10.1080/13543784.2022.2053107. Epub ahead of print. PMID: 35289234.

6: Cordero A, Ramsey MD, Kanojia D, Fares J, Petrosyan E, Schwartz CW, Burga R, Zhang P, Rashidi A, Castro B, Xiao T, Lee-Chang C, Miska J, Balyasnikova IV, Ahmed AU, Lesniak MS. Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. Proc Natl Acad Sci U S A. 2022 Jan 4;119(1):e2112491119. doi: 10.1073/pnas.2112491119. PMID: 34969858; PMCID: PMC8740706.

7: Curigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, Okines A, Paplomata E, Cameron D, Carey LA, Gelmon K, Hortobagyi GN, Krop I, Loibl S, Pegram M, Slamon D, Ramos J, Feng W, Winer E. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022 Mar;33(3):321-329. doi: 10.1016/j.annonc.2021.12.005. Epub 2021 Dec 23. PMID: 34954044.

8: O'Sullivan CC, Ballman KV, McCall L, Kommalapati A, Zemla T, Weiss A, Mitchell M, Blinder V, Tung NM, Irvin WJ, Lee M, Goetz MP, Symmans WF, Borges VF, Krop I, Carey LA, Partridge AH. Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. Future Oncol. 2021 Dec;17(34):4665-4676. doi: 10.2217/fon-2021-0753. Epub 2021 Oct 12. PMID: 34636255; PMCID: PMC8600597.

9: DeBusk K, Abeysinghe S, Vickers A, Nangia A, Bell J, Ike C, Forero-Torres A, Blahna MT. Efficacy of tucatinib for HER2-positive metastatic breast cancer after HER2-targeted therapy: a network meta-analysis. Future Oncol. 2021 Nov;17(33):4635-4647. doi: 10.2217/fon-2021-0742. Epub 2021 Aug 31. PMID: 34463120.

10: Tucatinib Is Active Against Brain Metastases in HER2+ Breast Cancer. Cancer Discov. 2020 Aug;10(8):1090. doi: 10.1158/2159-8290.CD- RW2020-087. Epub 2020 Jun 12. PMID: 34376460.

11: Dong L, Lin S, Zhong L, Nian D, Li Y, Wang R, Zhou W, Weng X, Xu X. Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis. Clin Breast Cancer. 2022 Jan;22(1):e21-e29. doi: 10.1016/j.clbc.2021.06.001. Epub 2021 Jun 12. PMID: 34238670.

12: Mueller V, Wardley A, Paplomata E, Hamilton E, Zelnak A, Fehrenbacher L, Jakobsen E, Curtit E, Boyle F, Harder Brix E, Brenner A, Crouzet L, Ferrario C, Muñoz-Mateu M, Arkenau HT, Iqbal N, Aithal S, Block M, Cold S, Cancel M, Hahn O, Poosarla T, Stringer-Reasor E, Colleoni M, Cameron D, Curigliano G, Siadak M, DeBusk K, Ramos J, Feng W, Gelmon K. Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial). Eur J Cancer. 2021 Aug;153:223-233. doi: 10.1016/j.ejca.2021.05.025. Epub 2021 Jun 29. PMID: 34214937.

13: Bonnemort J, Bellesoeur A. Nouvelles AMMs au niveau européen : tucatinib en association au trastuzumab et à la capecitabine dans les cancers du sein HER2+ métastatiques prétraités [New European Medicines Agency approval: Tucatinib in association with trastuzumab and capecitabine for the treatment of HER2-positive metastatic breast cancer previously treated]. Bull Cancer. 2021 Jul- Aug;108(7-8):673-675. French. doi: 10.1016/j.bulcan.2021.04.004. Epub 2021 Jun 23. PMID: 34172272.

14: Ulrich L, Okines AFC. Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib. Breast Cancer (Dove Med Press). 2021 May 26;13:361-381. doi: 10.2147/BCTT.S268451. PMID: 34079368; PMCID: PMC8164963.

15: Corti C, Criscitiello C. Tucatinib approval by EMA expands options for HER2-positive locally advanced or metastatic breast cancer. ESMO Open. 2021 Apr;6(2):100063. doi: 10.1016/j.esmoop.2021.100063. Epub 2021 Mar 3. PMID: 33676293; PMCID: PMC8103530.

16: Jing W, Zhou M, Chen R, Ye X, Li W, Su X, Luo J, Wang Z, Peng S. In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells. Oncol Rep. 2021 Mar;45(3):1142-1152. doi: 10.3892/or.2020.7915. Epub 2020 Dec 30. PMID: 33650639; PMCID: PMC7859976.

17: Kaur S, Bhattacharyya R, Banerjee D, Shukla J. Application of Tucatinib and Trastuzumab: Dual Anti HER2 Therapy Against HER2 Positive Breast Cancer. Indian J Clin Biochem. 2021 Jan;36(1):124-125. doi: 10.1007/s12291-019-00863-8. Epub 2019 Dec 5. PMID: 33505137; PMCID: PMC7817741.

18: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–. Tucatinib. 2021 Jan 18. PMID: 33226752.

19: Alsalme A, Pooventhiran T, Al-Zaqri N, Rao DJ, Rao SS, Thomas R. Modelling the structural and reactivity landscapes of tucatinib with special reference to its wavefunction-dependent properties and screening for potential antiviral activity. J Mol Model. 2020 Nov 16;26(12):341. doi: 10.1007/s00894-020-04603-1. PMID: 33200284; PMCID: PMC7668570.

20: Shah M, Wedam S, Cheng J, Fiero MH, Xia H, Li F, Fan J, Zhang X, Yu J, Song P, Chen W, Ricks TK, Chen XH, Goldberg KB, Gong Y, Pierce WF, Tang S, Theoret MR, Pazdur R, Amiri-Kordestani L, Beaver JA. FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. Clin Cancer Res. 2021 Mar 1;27(5):1220-1226. doi: 10.1158/1078-0432.CCR-20-2701. Epub 2020 Oct 14. PMID: 33055172.



Additional Information

  Note: As of 9/1/2015, there are several vendors listed ARRY-380 as a wrong structure.