Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model.

Vasilevich, Natalya I.; Tatarskiy Jr., Victor V.; Aksenova, Elena A.; Kazyulkin, Denis N.; Afanasyev, Ilya I.

Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3-5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines. Thus, we showed the possibility to fine-tune the general Ser/Thr pharmacophore to design active and selective compounds against desired types of kinases.

SERINE/THREONINE kinases; CANCER cells; CELL lines; PROTEIN kinase inhibitors; TUBERCULOSIS treatment

Pharmaceuticals (14248247), 2016, Vol 9, Issue 2, p19

1424-8247

Academic Journal

10.3390/ph9020019