A kinase-cGAS cascade to synthesize a therapeutic STING activator

John A. McIntosh (), Zhijian Liu (), Brian M. Andresen (), Nastaran Salehi Marzijarani, Jeffrey C. Moore, Nicholas M. Marshall, Margie Borra-Garske, Jennifer V. Obligacion, Patrick S. Fier, Feng Peng, Jacob H. Forstater, Matthew S. Winston, Chihui An, Wonsuk Chang, Jongwon Lim, Mark A. Huffman, Steven P. Miller, Fuh-Rong Tsay, Michael D. Altman, Charles A. Lesburg, Dietrich Steinhuebel, B. Wesley Trotter, Jared N. Cumming, Alan Northrup, Xiaodong Bu, Benjamin F. Mann, Mirlinda Biba, Kaori Hiraga, Grant S. Murphy, Joshua N. Kolev, Amanda Makarewicz, Weilan Pan, Iman Farasat, Rachel S. Bade, Kevin Stone, Da Duan, Oscar Alvizo, Donovan Adpressa, Erik Guetschow, Erik Hoyt, Erik L. Regalado, Steve Castro, Nelo Rivera, Joseph P. Smith, Fengqiang Wang, Alejandro Crespo, Deeptak Verma, Stephanus Axnanda, Zachary E. X. Dance, Paul N. Devine, David Tschaen, Keith A. Canada, Paul G. Bulger, Benjamin D. Sherry, Matthew D. Truppo, Rebecca T. Ruck, Louis-Charles Campeau, David Jonathan Bennett, Guy R. Humphrey, Kevin R. Campos and Matthew L. Maddess
Additional contact information
John A. McIntosh: Process Research & Development, Merck & Co., Inc.
Zhijian Liu: Process Research & Development, Merck & Co., Inc.
Brian M. Andresen: Discovery Chemistry, Merck & Co., Inc.
Nastaran Salehi Marzijarani: Process Research & Development, Merck & Co., Inc.
Jeffrey C. Moore: Process Research & Development, Merck & Co., Inc.
Nicholas M. Marshall: Process Research & Development, Merck & Co., Inc.
Margie Borra-Garske: Codexis, Inc.
Jennifer V. Obligacion: Process Research & Development, Merck & Co., Inc.
Patrick S. Fier: Process Research & Development, Merck & Co., Inc.
Feng Peng: Process Research & Development, Merck & Co., Inc.
Jacob H. Forstater: Process Research & Development, Merck & Co., Inc.
Matthew S. Winston: Process Research & Development, Merck & Co., Inc.
Chihui An: Process Research & Development, Merck & Co., Inc.
Wonsuk Chang: Discovery Chemistry, Merck & Co., Inc.
Jongwon Lim: Discovery Chemistry, Merck & Co., Inc.
Mark A. Huffman: Process Research & Development, Merck & Co., Inc.
Steven P. Miller: Process Research & Development, Merck & Co., Inc.
Fuh-Rong Tsay: Analytical Research & Development, Merck & Co., Inc.
Michael D. Altman: Discovery Chemistry, Merck & Co., Inc.
Charles A. Lesburg: Discovery Chemistry, Merck & Co., Inc.
Dietrich Steinhuebel: Process Research & Development, Merck & Co., Inc.
B. Wesley Trotter: Discovery Chemistry, Merck & Co., Inc.
Jared N. Cumming: Discovery Chemistry, Merck & Co., Inc.
Alan Northrup: Discovery Chemistry, Merck & Co., Inc.
Xiaodong Bu: Analytical Research & Development, Merck & Co., Inc.
Benjamin F. Mann: Analytical Research & Development, Merck & Co., Inc.
Mirlinda Biba: Analytical Research & Development, Merck & Co., Inc.
Kaori Hiraga: Process Research & Development, Merck & Co., Inc.
Grant S. Murphy: Process Research & Development, Merck & Co., Inc.
Joshua N. Kolev: Process Research & Development, Merck & Co., Inc.
Amanda Makarewicz: Process Research & Development, Merck & Co., Inc.
Weilan Pan: Process Research & Development, Merck & Co., Inc.
Iman Farasat: Process Research & Development, Merck & Co., Inc.
Rachel S. Bade: Process Research & Development, Merck & Co., Inc.
Kevin Stone: Process Research & Development, Merck & Co., Inc.
Da Duan: Codexis, Inc.
Oscar Alvizo: Codexis, Inc.
Donovan Adpressa: Discovery Chemistry, Merck & Co., Inc.
Erik Guetschow: Analytical Research & Development, Merck & Co., Inc.
Erik Hoyt: Analytical Research & Development, Merck & Co., Inc.
Erik L. Regalado: Process Research & Development, Merck & Co., Inc.
Steve Castro: Analytical Research & Development, Merck & Co., Inc.
Nelo Rivera: Analytical Research & Development, Merck & Co., Inc.
Joseph P. Smith: Analytical Research & Development, Merck & Co., Inc.
Fengqiang Wang: Analytical Research & Development, Merck & Co., Inc.
Alejandro Crespo: Process Research & Development, Merck & Co., Inc.
Deeptak Verma: Process Research & Development, Merck & Co., Inc.
Stephanus Axnanda: Analytical Research & Development, Merck & Co., Inc.
Zachary E. X. Dance: Analytical Research & Development, Merck & Co., Inc.
Paul N. Devine: Process Research & Development, Merck & Co., Inc.
David Tschaen: Process Research & Development, Merck & Co., Inc.
Keith A. Canada: Process Research & Development, Merck & Co., Inc.
Paul G. Bulger: Process Research & Development, Merck & Co., Inc.
Benjamin D. Sherry: Process Research & Development, Merck & Co., Inc.
Matthew D. Truppo: Process Research & Development, Merck & Co., Inc.
Rebecca T. Ruck: Process Research & Development, Merck & Co., Inc.
Louis-Charles Campeau: Process Research & Development, Merck & Co., Inc.
David Jonathan Bennett: Discovery Chemistry, Merck & Co., Inc.
Guy R. Humphrey: Process Research & Development, Merck & Co., Inc.
Kevin R. Campos: Process Research & Development, Merck & Co., Inc.
Matthew L. Maddess: Process Research & Development, Merck & Co., Inc.

Nature, 2022, vol. 603, issue 7901, 439-444

Abstract: Abstract The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1–3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.

Date: 2022
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DOI: 10.1038/s41586-022-04422-9

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