Discovery and characterization of potent and selective inhibitors of MASTL

Microtubule associated serine/threonine kinase-like (MASTL) is a first-in-class (FIC) target that represents a compelling opportunity to extend therapeutic control of mitotic checkpoints in the context of oncology. There are few literature-reported inhibitors of this kinase. Through multiple parameter optimization and iterative cycles of structure-based drug design and synthesis we have been able to deliver two clinical candidate quality analogs. Key challenges addressed in the course of the optimization were enhancement of potency and selectivity while balancing clearance and permeability. With highly potent and selective MASTL inhibitors in hand, we were able to show proof-of-concept for the therapeutic potential of this mechanism using a tumor-growth inhibition in vivo model.