Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5′-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC₅₀ values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4′- and the 5′-hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7′-C8′ double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.