Abstract C55: Discovery and optimization of inhibitors of the KIFC1 motor protein.

Abstract

KIFC1, a kinesin-14 family protein, plays an essential role in centrosomal bundling, a strategy employed by cancer cells to avoid multipolar mitosis in the presence of amplified centrosomes. However, its function is not required for normal diploid cell division, suggesting that KIFC1 is an attractive therapeutic target for human cancers. We have recently reported the first small molecule inhibitor of KIFC1, AZ82 [1]. AZ82 binds specifically to the KIFC1/microtubule (MT) binary complex, and inhibits the MT-stimulated KIFC1 enzymatic activity with a KI of 0.043 µM. AZ82 effectively engaged with the minus-end directed KIFC1 motor in HeLa cells to reverse the monopolar spindle phenotype induced by the inhibition of the plus end-directed kinesin Eg5 by AZD4877, consistent with what was observed with genetic knock down of KiFC1 by siRNA. Additionally, treatment with AZ82 caused centrosome declustering in BT-549 breast cancer cells with amplified centrosomes. Here we further describe the chemistry approach and related structure-activity relationships that led to the discovery of AZ82. [1] http://pubs.acs.org/doi/abs/10.1021/cb400186w Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C55. Citation Format: Michelle L. Lamb, Jiaquan Wu, Keith Mikule, Wendy Wang, Nancy Su, Philip Petteruti, Farzin Gharahdaghi, Erin Code, Xiahui Zhu, Kelly Jacques, Zhongwu Lai, Tao Zhang, David Boulay, Gurmit Grewal, Nicholas Keen, Bin Yang, Claudio Chuaqui, Claudio Chuaqui, Huawei Chen. Discovery and optimization of inhibitors of the KIFC1 motor protein. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C55.