2. Academic Validation
  3. Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe

Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe

  • J Med Chem. 2022 Mar 24;65(6):4972-4990. doi: 10.1021/acs.jmedchem.1c02030.
Nuria A Tamayo 1,  Matthew P Bourbeau 1,  Jennifer R Allen 1,  Kate S Ashton 1,  Jian Jeffrey Chen 1,  Matthew R Kaller 1,  Thomas T Nguyen 1,  Nobuko Nishimura 1,  Liping H Pettus 1,  Mary Walton 1,  Brian Belmontes 2,  Jodi Moriguchi 2,  Kui Chen 3,  John D McCarter 3,  Kelly Hanestad 2,  Grace Chung 2,  Maria Stefania S Ninniri 2,  Jan Sun 2,  Leszek Poppe 4,  Chris Spahr 4,  John Hui 4,  Lei Jia 5,  Tian Wu 6,  Upendra P Dahal 7,  Katheryne Z Edson 8,  Marc Payton 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 2 Oncology Research, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 3 Discovery Technologies, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 4 Discovery Attribute Sciences, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 5 Computational & Data Sciences, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 6 Pre-Pivotal Drug Product, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 7 Pharmacokinetics and Drug Metabolism, Amgen Research, 1120 Veterans Blvd., South San Francisco, California 94080, United States.
  • 8 Pharmacokinetics and Drug Metabolism, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 35286090 DOI: 10.1021/acs.jmedchem.1c02030
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 23 and 24 caused significant mitotic arrest in vivo, which was sustained for 24 h. This would be followed by cell death either in mitosis or in the subsequent interphase. Furthermore, photoaffinity labeling experiments reveal that this series of inhibitors binds at the interface of KIF18A and tubulin. This study represents the first disclosure of KIF18A inhibitors with in vivo activity.

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