Discovery and Optimization of LATS1 and LATS2 Kinase Inhibitors for Use in Regenerative Medicine

The Large Tumor Suppressor Kinases 1 and 2 (LATS1/2) are serine/threonine kinases that play an essential role in Hippo pathway activation and influence multiple physiological events ranging from organ growth to tissue regeneration. As a result, pharmacological inhibition of LATS1/2 represents a promising strategy for therapeutic intervention in multiple indications. Within, we present the discovery of potent and selective inhibitors of the kinases LATS1 and LATS2. Using a scaffold hopping strategy from the reported AKT inhibitor AT-7867 (1) we pursued a series of structure activity relationship (SAR) studies that dramatically improved potency versus LATS1 and LATS2, while concurrently improving kinome-wide selectivity. ADME properties were further optimized via introduction of conformational restriction into the target molecule, to lead to compound 27 which possesses potent inhibitory activity against both LATS1 and LATS2 and proof of concept activity in wound healing models.