This talk highlights the discovery and chemical development of MK-1454, a cyclic dinucleotide STING agonist that has been evaluated in clinical trials as an immune stimulant for the treatment of solid tumors. In this session, we present a highly diastereoselective synthesis of MK-1454 which begins with the novel, asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. Finally, from these complex subunits, a novel thiophosphorylation reaction and a multi-step biocatalytic cascade enabled by the directed evolution of engineered enzymes were developed, providing a diastereoselective synthesis of this complex structure in unprecedented yield and efficiency.

Discovery and development of MK-1454, a therapeutic cyclic dinucleotide STING agonist

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