Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships

Asquith, C. R. M.; East, M. P.; Laitinen, T.; Alamillo-Ferrer, C.; Hartikainen, E.; Wells, C. I.; Axtman, A. D.; Drewry, D. H.; Tizzard, G. J.; Poso, A.; Willson, T. M.; Johnson, G. L.

doi:10.1101/2023.12.28.573261

bioRxiv · 10.1101/2023.12.28.573261

Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships

Asquith, C. R. M.·East, M. P.·Laitinen, T.·Alamillo-Ferrer, C.·Hartikainen, E.·Wells, C. I.·Axtman, A. D.·Drewry, D. H.·Tizzard, G. J.·Poso, A.·Willson, T. M.·Johnson, G. L.

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Abstract

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole as long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesized a large series of analogues and through quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, small-molecule x-ray structural analysis and kinome profiling, narrow spectrum, sub-family selective, chemical tool compounds were identified to enable elucidation of TLK2 biology.

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Asquith, C. R. M., East, M. P., Laitinen, T., Alamillo-Ferrer, C., Hartikainen, E., Wells, C. I., Axtman, A. D., Drewry, D. H., Tizzard, G. J., Poso, A., Willson, T. M., Johnson, G. L.. 2023-12-28. Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships. https://doi.org/10.1101/2023.12.28.573261

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