A series of selective TNNI3K inhibitors were developed by modifying the hinge-binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250-fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies.
Keywords: B-Raf; Kinase selectivity; Quinazoline; Substituent effects; TNNI3K.
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