Abstract
SummaryCentrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics.
Highlights
DNA replication, followed by equal chromosome segregation, ensures the accurate transmission of the genetic information to daughter cells (Hall et al, 2003; Nigg, 2002; Zyss and Gergely, 2009)
Centrosomes associate with spindle poles; the presence of two centrosomes promotes bipolar spindle assembly in normal cells
Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET
Summary
DNA replication, followed by equal chromosome segregation, ensures the accurate transmission of the genetic information to daughter cells (Hall et al, 2003; Nigg, 2002; Zyss and Gergely, 2009). In the assembly of a functional mitotic spindle, microtubule (MT) motor proteins play a central role (Cai et al, 2010; Ganem and Compton, 2004) One such protein, HSET (encoded by KIFC1 in humans and Kifc5a in mice), a minus-end MT motor, is of interest in cancer due to its impact on cell division (Cai et al, 2010; Goshima et al, 2005), and the discovery of a small-molecule inhibitor of HSET forms the focus of this study. Centrosome clustering may prove to be the Achilles heel of cancer cells with supernumerary centrosomes (Basto et al, 2008), and a growing body of evidence suggests that inhibition of centrosome clustering could provide a new therapeutic strategy for tumors with a high incidence of centrosome amplification (Jordan and Wilson, 2004; Ogden et al, 2012). In this work, we hypothesized that inhibition of centrosome clustering could provide an alternative approach to cancer treatment
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