Abstract
Introduction of a 1-benzyl-1H-pyrazol-4-yl moiety at C7 of the imidazo[4,5-b]pyridine scaffold provided 7a which inhibited a range of kinases including Aurora-A. Modification of the benzyl group in 7a, and subsequent co-crystallisation of the resulting analogues with Aurora-A indicated distinct differences in binding mode dependent upon the pyrazole N-substituent. Compounds 7a and 14d interact with the P-loop whereas 14a and 14b engage with Thr217 in the post-hinge region. These crystallographic insights provide options for the design of compounds interacting with the DFG motif or with Thr217.
Highlights
Introduction of a pF substituent in the phenyl ring of 7a provided compound 7b which displayed a similar Aurora-A/B inhibitory profile, and human liver microsomal stability to that of 7a
We have previously reported imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases including 1 (CCT137690),[10] the dual FLT3/Aurora kinase inhibitor 2 (CCT241736),[11] and compound 3 which selectively inhibits Aurora-A over Aurora-B12 (Fig. 1)
We report ligand/Aurora-A protein crystallographic data that show different orientations for the substituent on the pyrazole ring suggesting that the 7-(pyrazol-4-yl)3H-imidazo[4,5-b]pyridine scaffold could be utilised for the design of compounds that interact with the DFG motif or with Thr[217], the latter tactic has been demonstrated to enhance AuroraA over Aurora-B selectivity.[12]
Summary
Introduction of a pF substituent in the phenyl ring of 7a provided compound 7b which displayed a similar Aurora-A/B inhibitory profile, and human liver microsomal stability to that of 7a. Introduction of a 1-benzyl-1H-pyrazol-4-yl moiety at C7 of the imidazo[4,5-b]pyridine scaffold provided 7a which inhibited a range of kinases including Aurora-A.
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