Description
Tucatinib is also known as ARRY-380 or Irbinitinib. ARRY-380 is an orally inhibitor of human epidermal growth factor receptor tyrosine kinase ErbB-2 (also called HER2) with potential antineoplastic activity. It 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. Therefore, ARRY-380 may be an alternative treatmentmethod for the treatment of HER2+ cancers.
Characteristics
Year of discovery: 2006
Year of introduction: 2020
Discovered by: Array BioPharma
Developed by: Array BioPharma
Primary targets: HER2
Binding type: I/II
Class: receptor tyrosine kinase
Treatment: HER2-positive breast cancer
Other names: ONT-380, ARRY-380
Oral bioavailability = not reported
Elimination half-life = 5.4 hours
Protein binding = 97%
Uses
Tucatinib, a highly selective HER2 inhibitor, was approved in 2020 as a combination therapy with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Mode of action
Tucatinib binds to tyrosine kinase (an enzyme) of HER2, reducing PI3-kinase and MAP-kinase signaling. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
References
[1] PATRICE A LEE. In VivoActivity of ARRY-380, a Potent, Small Molecule Inhibitor of ErbB2 in Combination with Trastuzumab, Docetaxel or Bevacizumab.[J]. Cancer research, 2009, 69 1: 5104-5104. DOI:
10.1158/0008-5472.SABCS-09-5104.
[2] S. MOULDER. Abstract A143: ARRY-380, a selective HER2 inhibitor: From drug design to clinical evaluation.[J]. Molecular Cancer Therapeutics, 2011, 10 1. DOI:
10.1158/1535-7163.TARG-11-A143.
[3] V. DINKEL. Abstract 852: ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice[J]. Cancer research, 2012, 72 1: 852-852. DOI:
10.1158/1538-7445.AM2012-852.
[4] KOCIE?SKI P. Synthesis of Tucatinib[J]. Synfacts, 2019, 24 1: 0965. DOI:
10.1055/s-0039-1690496.
[5] RASHMI K MURTHY. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.[J]. New England Journal of Medicine, 2020, 382 7: 597-609. DOI:
10.1056/NEJMoa1914609.
[6] RASHMI MURTHY. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.[J]. Lancet Oncology, 2018: 880-888. DOI:
10.1016/S1470-2045(18)30256-0.
