Discovery of Potent KIFC1 Inhibitors Using a Method of Integrated High-Throughput Synthesis and Screening

Yang, Bin; Lamb, Michelle L.; Zhang, Tao; Hennessy, Edward J.; Grewal, Gurmit; Li, Sha; Zambrowski, M.; Block, Michael H.; Dowling, James E.; Su, Nancy; Wu, Joy T.; Deegan, Tracy L.; Mikule, Keith; Wang, Wenxian; Kaspera, Rüdiger; Chuaqui, Claudio; Chen, Huawei

doi:10.1021/jm501179r

Cited by 34 publications

(31 citation statements)

References 36 publications

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“…To date, only two groups have reported specific KIFC1 inhibitors in the literature (37,43,44). Scientists at AstraZeneca identified a small molecule KIFC1 inhibitor, AZ82, which inhibited MT-stimulated KIFC1 ATPase activity with an IC 50 of 0.3 μM and triggered multipolar spindle formation and mitotic catastrophe in cells with amplified centrosomes.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel inhibitor of kinesin-like protein KIFC1

Zhang

Zhai

Wang

et al. 2016

Biochemical Journal

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Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast to normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selectively killing of cancer cells. In the present study, we identified a small molecule KIFC1 inhibitor, SR31527, which inhibited microtubule-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 μM. By using bio-layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity (Kd = 25.4 nM). Our results from computational modeling and STD-NMR experiment suggested that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra-centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Discovery of a novel inhibitor of kinesin-like protein KIFC1

Zhang

Zhai

Wang

et al. 2016

Biochemical Journal

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“…The AZ82 inhibitor of HSET was a gift from AstraZeneca (USA) [29][30]. AZ82 was stored diluted in DMSO at 100 lM and further diluted in M2 medium to a final concentration of 10 lM.…”

Section: Drug Treatmentmentioning

confidence: 99%

Shifting meiotic to mitotic spindle assembly in oocytes disrupts chromosome alignment

et al. 2018

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Mitotic spindles assemble from two centrosomes, which are major microtubule‐organizing centers (MTOCs) that contain centrioles. Meiotic spindles in oocytes, however, lack centrioles. In mouse oocytes, spindle microtubules are nucleated from multiple acentriolar MTOCs that are sorted and clustered prior to completion of spindle assembly in an “inside‐out” mechanism, ending with establishment of the poles. We used HSET (kinesin‐14) as a tool to shift meiotic spindle assembly toward a mitotic “outside‐in” mode and analyzed the consequences on the fidelity of the division. We show that HSET levels must be tightly gated in meiosis I and that even slight overexpression of HSET forces spindle morphogenesis to become more mitotic‐like: rapid spindle bipolarization and pole assembly coupled with focused poles. The unusual length of meiosis I is not sufficient to correct these early spindle morphogenesis defects, resulting in severe chromosome alignment abnormalities. Thus, the unique “inside‐out” mechanism of meiotic spindle assembly is essential to prevent chromosomal misalignment and production of aneuploidy gametes.

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“…In addition to the CuAAC reaction, various other reactions are available, including copper-free click reactions [79,80], thiol-ene click chemistry [81], metal-mediated amine-to-nitrile addition [84], amide-forming reaction [85,86], epoxide opening [87] and many other reactions for click chemistry [88]; and many of these are rapid, highly Owing to their excellent specificity and rapid reaction rate, we anticipate that many of these newly disclosed reactions will be effective substitutes for CuAAC and, in combination with HT in situ assay technologies, will further revolutionize lead-finding and lead-optimization campaigns in drug discovery.…”

Section: Page 14 Of 30mentioning

confidence: 99%