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KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics.

ABSTRACT: Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical-trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an uncharacterized, commercially available, small-molecule inhibitor, on KIF15 motility. To explore the complementary behaviors of KIF15 and Eg5, we also scored the effects of small-molecule inhibitors on admixtures of both motors, using both a microtubule (MT)-gliding assay and an assay for cancer cell viability. We found that (i) KIF15 motility differs significantly from Eg5; (ii) KIF15-IN-1 is a potent inhibitor of KIF15 motility; (iii) MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited; and (iv) pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth. Taken together, our results lend support to the notion that a combination drug therapy employing both inhibitors may be a viable strategy for overcoming chemotherapeutic resistance.

SUBMITTER: Milic B

PROVIDER: S-EPMC5960320 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics.

Milic Bojan B Chakraborty Anirban A Han Kyuho K Bassik Michael C MC Block Steven M SM

Proceedings of the National Academy of Sciences of the United States of America 20180427 20

Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical-trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an ...[more]

PMID: 29703754

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KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics.

Publications

KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics.

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