Definition

An orally bioavailable small molecule inhibitor of checkpoint kinase 1 (chk1), with potential antineoplastic and chemosensitization activities. Upon oral administration, chk1 inhibitor BBI-355 selectively binds to chk1, thereby preventing activity of chk1 and abrogating the repair of damaged DNA. This may lead to an accumulation of damaged DNA, inhibition of cell cycle arrest, and induction of apoptosis. BBI-355 may potentiate the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapeutic agents by targeting extrachromosomal DNA (ecDNA) originating from oncogene amplified cancer cells. Cancer cells that rely on oncogene amplification to grow and survive are highly sensitive to chk1 inhibition. Chk1, an ATP-dependent serine/threonine kinase, mediates cell cycle checkpoint control, is essential for DNA repair, and plays a key role in resistance to chemotherapeutic agents.