A Chemoenzymatic Synthesis of STING Agonist MK-2118

Pharmaceutical companies are increasingly leveraging the power of biocatalysis to enable the development of concise and robust commercial manufacturing processes for their therapeutics. Yet, implementation of biocatalysis via protein engineering often requires years to generate a production-ready enzyme. To enable rapid clinical supply, we engineered an enoate-reductase (ERED) to catalyze a key asymmetric reduction in a concise 4-step chemoenzymatic route toward the orally bioavailable STING agonist MK-2118. Within 2 months, we evolved a Z-selective ERED with high activity that delivered the desired product in high yield and exquisite enantioselectivity. The 4-step chemoenzymatic process was used to successfully deliver >10 kg of MK-2118 from readily available starting materials at 40% overall yield and >99% ee to accelerate clinical trials.