Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity.

Autor: Uitdehaag JCM; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., de Man J; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Willemsen-Seegers N; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Prinsen MBW; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Libouban MAA; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Sterrenburg JG; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., de Wit JJP; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., de Vetter JRF; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., de Roos JADM; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Buijsman RC; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands., Zaman GJR; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands. Electronic address: guido.zaman@ntrc.nl.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2017 Jul 07; Vol. 429 (14), pp. 2211-2230. Date of Electronic Publication: 2017 May 21.
DOI: 10.1016/j.jmb.2017.05.014
Abstrakt: The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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