Discovery and Chemical Development of Uvelostinag (MK-1454): A Therapeutic Cyclic Dinucleotide Agonist of the Stimulator of Interferon Gene

This chapter highlights the discovery and chemical development of MK-1454, a cyclic dinucleotide STING agonist that has progressed to clinical trials as an immune stimulant for the treatment of solid tumors. The medicinal chemistry effort that culminated in the discovery of MK-1454 leveraged X-ray crystallography, modeling, and a variety of synthetic innovations including biocatalytic synthesis, to enable evaluation of a large number of cyclic dinucleotides for STING agonist activity. Additional innovation in P(III) chemistry enabled delivery of clinical supply, overcoming many challenges associated with the intrinsic complexity of this phosphorothioate cyclic dinucleotide drug candidate. Finally, a multi-step biocatalytic cascade enabled by directed evolution of an engineered animal cGAS (cyclic guanosine adenosine synthase) was developed, providing a diastereoselective, single pot synthesis of this complex structure in extremely high yield and efficiency.