title: Discovery of a novel inhibitor of kinesin-like protein KIFC1.
abstract: 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 with 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 selective killing of cancer cells. In the present study, we identified a small-molecule KIFC1 inhibitor, SR31527, which inhibited microtubule (MT)-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 modelling and saturation-transfer difference (STD)-NMR experiments suggest 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.
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A. wzhang@southernresearch.org.
authors: Wei
authors: W
authors: Zhang
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Ling
authors: L
authors: Zhai
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Yimin
authors: Y
authors: Wang
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Rebecca J
authors: RJ
authors: Boohaker
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Wenyan
authors: W
authors: Lu
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Vandana V
authors: VV
authors: Gupta
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Indira
authors: I
authors: Padmalayam
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Robert J
authors: RJ
authors: Bostwick
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: E Lucile
authors: EL
authors: White
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Larry J
authors: LJ
authors: Ross
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Joseph
authors: J
authors: Maddry
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Subramaniam
authors: S
authors: Ananthan
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Corinne E
authors: CE
authors: Augelli-Szafran
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Mark J
authors: MJ
authors: Suto
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Bo
authors: B
authors: Xu
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Rongbao
authors: R
authors: Li
authors: Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, U.S.A.
authors: Yonghe
authors: Y
authors: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D013830:Thiadiazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C486566:KIFC1 protein, human; C000609927:SR31527; D013830:Thiadiazoles; D016547:Kinesins
keywords: allosteric regulation; breast cancer; inhibitor; kinesin; mitosis