tucatinib   Click here for help

GtoPdb Ligand ID: 9922

Synonyms: ARRY-380 | Example 11 [WO2007059257A2] | ONT-380 | Tukysa®
Approved drug
tucatinib is an approved drug (FDA (2020), EMA (2021))
Compound class: Synthetic organic
Comment: Tucatinib is an orally bioavailable ERBB2 (HER2) receptor tyrosine kinase inhibitor that was developed as a novel antineoplastic agent by Seattle Genetics [2]. The chemical structure is claimed as Example 11 in Array Biopharma patent WO2007059257A2 [3], and was exemplified as ARRY-380 in the later patent WO2013056183A1 [1]. Tucatinib contains a quinazoline core that is conserved in other tyrosine kinase inhibitors including lapatinib, erlotinib, and gefitinib [2].
The INN tucatinib replaced the earlier INN irbinitinib that was associated with this chemical entity.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 110.85
Molecular weight 480.2
XLogP 3.75
No. Lipinski's rules broken 0
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Canonical SMILES Cc1cc(ccc1Oc1ccn2c(c1)ncn2)Nc1ncnc2c1cc(cc2)NC1=NC(CO1)(C)C
Isomeric SMILES Cc1cc(ccc1Oc1ccn2c(c1)ncn2)Nc1ncnc2c1cc(cc2)NC1=NC(CO1)(C)C
InChI 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)
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Summary of Clinical Use Click here for help
Early clinical trial data indicated that tucatinib produced marked antitumour activity in heavily pretreated HER2+ve metastatic breast cancer patients, and some of the side effects were diminished in comparison to contemporary dual HER2/EGFR inhibitors [4]. Several Phase 2 studies in breast cancer and other cancers with ERBB2 gene amplification were undertaken. Click here to link to the complete list of tucatinib trials that are registered at ClinicalTrials.gov.
A FDA New Drug Application for tucatinib for locally advanced or metastatic HER2+ve breast cancer was submitted by Seattle Genetics in December 2019. The first full FDA approval was granted in April 2020. Under this approval tucatinib was indicated for advanced unresectable or metastatic HER2+ve breast cancer (including brain metastases) in combination with trastuzumab and capecitabine, in patients who had received ≥1 prior anti-HER2-based regimens for metastatic disease. In early 2023, the FDA issued accelerated approval for combined treatment with tucatinib plus trastuzumab for colorectal cancer (specifically for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer), that has progressed after FOLFOXIRI chemotherapy (a fluoropyrimidine, oxaliplatin, and irinotecan). This decision was based on data from the MOUNTAINEER study (NCT03043313).
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT03043313 Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer Phase 2 Interventional Seagen Inc.