1. Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe
- Author
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Nuria A. Tamayo, Matthew P. Bourbeau, Jennifer R. Allen, Kate S. Ashton, Jian Jeffrey Chen, Matthew R. Kaller, Thomas T. Nguyen, Nobuko Nishimura, Liping H. Pettus, Mary Walton, Brian Belmontes, Jodi Moriguchi, Kui Chen, John D. McCarter, Kelly Hanestad, Grace Chung, Maria Stefania S. Ninniri, Jan Sun, Leszek Poppe, Chris Spahr, John Hui, Lei Jia, Tian Wu, Upendra P. Dahal, Katheryne Z. Edson, and Marc Payton
- Subjects
Cell Death ,Tubulin ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Humans ,Kinesins ,Mitosis ,Spindle Apparatus - Abstract
Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting of CIN-associated vulnerabilities is an emerging therapeutic strategy in drug development. KIF18A, a mitotic kinesin, has been shown to play a role in maintaining bipolar spindle integrity and promotes viability of CIN cancer cells. To explore the potential of KIF18A, a series of inhibitors was identified. Optimization of an initial hit led to the discovery of analogues that could be used as chemical probes to interrogate the role of KIF18A inhibition. Compounds
- Published
- 2022