Abstract:
Discovery and Development of MK-1454, a Therapeutic Cyclic Dinucleotide Sting Agonist
Matthew Maddess,*,a on behalf of the broader Merck Discovery and Development teams.b
aDistinguished Scientist, Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, USA
bDiscovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States
High levels of attrition of drug candidates as they progress through development exerts a large negative drag on return on investment of research expenditures. Strategies that mitigate risk prior to entry to the clinic, in addition to speed to go/no go decisions once clinical trials have started, invariably puts physical supply of the advanced pharmaceutical ingredient (API) on critical path and the need for efficient phase appropriate syntheses is a high priority. With this business driver, development functions such as Process Chemistry have established themselves as valued team members on Discovery teams. This is discussed in the context of the MK-1454 program, a cyclic dinucleotide STING agonist that is being evaluated in 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. In line with the Process Research and Development’s strategy of identifying the most direct route from commodity raw materials to API, a convergent 13-step (8 step longest linear sequence) to MK-1454 was developed, featuring innovative carbohydrate and fluorine chemistry to access the nucleoside monomers and a remarkable biocatalytic approach to their union by leveraging the directed evolution of a naturally occurring cGAS enzyme. Early identification of chemistry issues associated with compounds of interest through partnership between Discovery and Process Chemistry improves the speed of execution, the transition to development, and our mission of delivering the best process at first filing. This presentation will cover the end-to-end history of the program and highlight key innovations along the way.
References:
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