TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models

Molecular Cancer Therapeutics
Hiroki IrieKenichi Matsuo

Abstract

Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal-dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken ...Continue Reading

References

Aug 15, 1997·The Biochemical Journal·G M Cohen
Jul 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Thomas HolbroNancy E Hynes
Jul 20, 2007·Nature Reviews. Drug Discovery·Beverly MoyPaul Goss
Feb 20, 2008·Annals of Oncology : Official Journal of the European Society for Medical Oncology·H J BursteinK L Blackwell
Feb 25, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zev A WainbergRichard S Finn
Apr 8, 2010·Science Translational Medicine·Dhara N AminMark M Moasser
Jul 13, 2012·Nature Reviews. Cancer·Yosef Yarden, Gur Pines
Mar 20, 2013·Expert Review of Anticancer Therapy·James Chih-Hsin YangEzra E W Cohen
Mar 25, 2014·Cancer Treatment Reviews·Min YanRazelle Kurzrock
Apr 9, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·A Jo ChienMark M Moasser
Jan 23, 2015·World Journal of Clinical Cases·Tasuku Matsuoka, Masakazu Yashiro
Dec 13, 2016·Lancet·Sibylle Loibl, Luca Gianni
Apr 21, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·L Paz-AresK Park
Jun 7, 2017·The New England Journal of Medicine·Solange PetersUNKNOWN ALEX Trial Investigators
Dec 7, 2017·ESMO Open·Claire M Connell, Gary J Doherty
Feb 22, 2018·The New England Journal of Medicine·Alexander DrilonDavid M Hyman

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.