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Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-14 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-14 , 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
Affiliation
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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.
中文翻译：
针对染色体不稳定癌症中的有丝分裂驱动蛋白 KIF18A：实现体内化学探针的优化
染色体不稳定性 (CIN) 是癌症的标志，它是由有丝分裂期间染色体分离错误引起的。针对 CIN 相关的脆弱性是药物开发中新兴的治疗策略。KIF18A 是一种有丝分裂驱动蛋白，已被证明在维持双极纺锤体完整性和促进 CIN 癌细胞活力方面发挥作用。为了探索 KIF18A 的潜力，鉴定了一系列抑制剂。对初始命中的优化导致发现了可用作化学探针来询问 KIF18A 抑制作用的类似物。化合物23和24在体内引起显着的有丝分裂停滞，持续 24 小时。这将在有丝分裂或随后的间期发生细胞死亡。此外，光亲和标记实验表明，这一系列抑制剂结合在 KIF18A 和微管蛋白的界面上。该研究首次公开了具有体内活性的 KIF18A 抑制剂。
更新日期：2022-03-14
中文翻译：
针对染色体不稳定癌症中的有丝分裂驱动蛋白 KIF18A：实现体内化学探针的优化
染色体不稳定性 (CIN) 是癌症的标志，它是由有丝分裂期间染色体分离错误引起的。针对 CIN 相关的脆弱性是药物开发中新兴的治疗策略。KIF18A 是一种有丝分裂驱动蛋白，已被证明在维持双极纺锤体完整性和促进 CIN 癌细胞活力方面发挥作用。为了探索 KIF18A 的潜力，鉴定了一系列抑制剂。对初始命中的优化导致发现了可用作化学探针来询问 KIF18A 抑制作用的类似物。化合物23和24在体内引起显着的有丝分裂停滞，持续 24 小时。这将在有丝分裂或随后的间期发生细胞死亡。此外，光亲和标记实验表明，这一系列抑制剂结合在 KIF18A 和微管蛋白的界面上。该研究首次公开了具有体内活性的 KIF18A 抑制剂。
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