Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin.

The approval of histone deacetylase inhibitors for treatment of lymphoma subtypes has positioned histone modifications as potential targets for the development of new classes of anticancer drugs. Histones also undergo phosphorylation events, and Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph), which is necessary for mitosis progression. Mitotic kinases can be blocked by small drugs and several clinical trials are underway with these agents. As occurs with Aurora kinase inhibitors, Haspin might be an optimal candidate for the pharmacological development of these compounds. A high-throughput screening for Haspin inhibitors identified the CHR-6494 compound as being one promising such agent. We demonstrate that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly, ex vivo assays also demonstrate its anti-angiogenetic features; in vivo, it shows antitumor potential in xenografted nude mice without any observed toxicity. Thus, CHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects that merits further preclinical research as a new member of the family of mitotic kinase inhibitors.

Change of the reaction pattern by methodological variations in a multicomponent assembly promoted by Ni complexes.

The pi-allylnickel complex formed by the addition of trimethylsilyl chloride (TMSCl) to a mixture of [Ni-(cod)2] (cod = 1,5-cyclooctadiene) and a vinyl ketone (Mackenzie complex) carbometalates an acetylene in a completely regioselective manner resulting in the formation of the corresponding vinyl nickel species. This intermediate is capable of controlled quenching in a variety of ways to give different types of compounds: under a CO atmosphere, an acylnickel species is formed that ensues from the carbometalation of the enol ether double bond to form cyclo-pentenone derivatives. Alternatively, if acetylene is present in excess and CO is absent, another acetylene moiety will replace the CO and cyclohexadienes will result instead. Finally, if only an excess of the vinyl ketone is used, the product from a slow double addition of the vinyl ketone across the triple bond is formed. The regioselectivities obtained by the present method are different from those obtained by the involvement of nickel acyclopentadienes as intermediates when the order of addition is reversed.