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Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In vitro Assay.

INTRODUCTION
Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. TTK targeting received recent concern for the enhancement of possible anticancer therapies.


OBJECTIVE
In this regard we employed our well-known method of QSAR-guided selection of best crystallographic pharmacophore(s) to discover considerable binding interactions that anchore inhibitors into TTK1 binding site.


METHOD
Sixtyone TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that when combined with other physicochemical descriptors elucidates bioactivity discrepancy within a list of 55 miscellaneous inhibitors.


RESULTS
The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors.


CONCLUSION
Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 micM.