Histone modification, a post-translational modification of histones and involving various covalent tags, such as methyl, phosphate and acetate groups, affects gene expression and hence modulates various cellular events, including growth and proliferation. Consequently histone-modifying proteins have become targets for the development of anticancer agents. Thus far, compounds that inhibit the methylation or acetylation of histones have advanced in the clinic, but inhibitors of histone phosphorylation have lagged behind. Haspin is a kinase that phosphorylates histone H3 and is a promising anticancer target. Thus far only a handful of haspin inhibitors have been reported. Using a one-flask Doebner/Povarov reaction, we synthesized a library of compounds that potently inhibit haspin with IC50 values as low as 14 nM. Some of these compounds also inhibited the proliferation of cancer cell lines HCT116, HeLa and A375. The ease of synthesis of the new haspin inhibitors, coupled with their anticancer activities make these compounds interesting leads to develop into therapeutics.
Keywords: Doebner/Povarov reaction; Haspin; Kinase inhibitor.
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