KIF18A is a mitotic kinesin that plays a key role in maintaining bipolar spindle integrity and promotes viability of chromosomally unstable aneuploid cancer cells. KIF18A is overexpressed in a subset of cancers, and its elevated expression is associated with advanced tumor grade and metastasis. The rationale for pharmacological inhibition of KIF18A is to selectively target a cancer-specific mitotic vulnerability while largely sparing normal somatic cells, thereby acting as a highly focal cytotoxic drug. Here we describe our screening, hit finding, and lead optimization efforts to identify the clinical candidate AMG 650, a first-in-class small molecule inhibitor of KIF18A. AMG 650 is a highly potent, orally bioavailable inhibitor of KIF18A, that shows robust anti-tumor activity in TP53 mutant human cancer xenograft mouse models. AMG 650 binds to the complex formed by the motor domain of KIF18A and tubulin, exploiting unique interactions in this ternary complex. AMG 650 has advanced to Phase I clinical testing in patients with advanced solid tumors that harbor TP53 genetic mutations.

Discovery of AMG 650, a first-in-class KIF18A inhibitor for the treatment of chromosomally unstable cancers

ACS Spring 2022

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