Definition

An orally bioavailable, brain-penetrable inhibitor of ataxia telangiectasia mutated (ATM) kinase, with potential chemo-and radio-sensitizing and antineoplastic activities. Upon oral administration, ATM kinase inhibitor WSD-0628 selectively targets and binds to ATM, thereby inhibiting the kinase activity of ATM and ATM-mediated signaling. This prevents DNA damage checkpoint activation, disrupts DNA damage repair, induces apoptosis in damaged tumor cells, and leads to cell death in ATM-overexpressing tumor cells. WSD-0628 hypersensitizes tumors to chemo/radiotherapy. In addition, WSD-0628 is able to cross the blood-brain barrier (BBB). ATM, a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinases, is upregulated in a variety of cancer cell types. It is activated in response to DNA double-strand breaks (DSB) and plays a key role in DNA repair.