Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.
Christopher R M AsquithMichael P EastTuomo LaitinenCarla Alamillo-FerrerErkka HartikainenCarrow I WellsAlison D AxtmanDavid Harold DrewryGraham J TizzardAntti PosoTimothy M WillsonGary L JohnsonPublished in: bioRxiv : the preprint server for biology (2023)
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 has 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.
Keyphrases
- small molecule
- structure activity relationship
- high resolution
- protein kinase
- drug discovery
- tyrosine kinase
- systematic review
- molecular docking
- public health
- high throughput
- molecular dynamics
- protein protein
- magnetic resonance imaging
- mass spectrometry
- health insurance
- molecular dynamics simulations
- drug administration