B-Raf kinase inhibitors: Hit enrichment through scaffold hopping

In continuation of our efforts toward hit identification and optimization for a B-Raf kinase project, we have employed a scaffold hopping strategy. The original HTS hit scaffold pyrazolo[1,5-a]pyrimidine was replaced with different thienopyrimidine and thienopyridine scaffolds to append the optimal pharmacophore moieties in order to generate novel B-raf kinase inhibitors with desirable potency and properties. This strategy led to the identification of additional lead compound 11b which had good enzyme and cell potency, while maintaining selectivity over a number of kinases.

Graphical abstractScaffold hopping strategy was employed to replace the HTS hit scaffold pyrazolo[1,5-a]pyrimidine. This strategy led to the identification of additional lead compound 11b with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.Figure optionsDownload full-size imageDownload as PowerPoint slide