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.