Discovery of MK-1088 as a Potent A2A/A2B Adenosine Receptor Dual-Antagonist for Cancer Immunotherapy

  • J Med Chem. 2026 May 14;69(9):10338-10359. doi: 10.1021/acs.jmedchem.5c03405.
Yonglian Zhang  1 ,  Elisabeth Hennessy  2 ,  Matthew A Larsen ,  Jingsong Hao  1 ,  Jianping Pan  1 ,  Umar Faruk Mansoor  2 ,  Aaron Sather  3 ,  Zachary G Brill ,  Lorena Rico ,  Uma Swaminathan ,  Jesus Moreno ,  Brandon A Vara ,  Sheila Ranganath ,  Anthony Palmieri  4 ,  Oluwaseun Ogunbodede  3 ,  Evan R Barry  5 ,  Marlene C Hinton  5 ,  Pierre Daublain ,  Pranav Gupta ,  Manash Chatterjee ,  Sylvie Rottey  6 ,  Jeremy Presland  5 ,  Armetta D Hill  5 ,  William J Dewey  5 ,  Sebastian E Schneider  2 ,  Paul J Ciaccio ,  Karin M Otte ,  Diane Rindgen ,  Daniel Tatosian ,  Ben W H Turnbull  3 ,  Steven M Silverman  3 ,  Harry Chobanian ,  Harini Krishnamurthy  7 ,  Ling Pang  8 ,  Richard Wnek  8 ,  Roshi Afshar ,  Stephen Crowley  9 ,  Alita Miller  9 ,  Jennifer O'Neil ,  Jill Chrencik ,  Christopher W Plummer  1 ,  Amjad Ali  1 ,  Jared Cumming ,  Duane E DeMong  2
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., 126 E Lincoln Avenue, Rahway, New Jersey 07065, United States.
  • 2. Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 3. Department of Process Research and Development, Merck & Co., Inc., 126 E Lincoln Avenue, Rahway, New Jersey 07065, United States.
  • 4. Discovery Oncology, Discovery Oncology, MerckMerck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 5. Quantitative Biosciences, LMerck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 6. Drug Research Unit Ghent, Ghent 9000, Belgium.
  • 7. Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 8. Translational Medicine, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
  • 9. Oral Formulation Sciences, Merck & Co., Inc., 126 E Lincoln Avenue, Rahway, New Jersey 07065, United States.
PMID: 42084562 DOI: 10.1021/acs.jmedchem.5c03405
Abstract

Immune cells expressing the adenosine A2A receptor (A2AR) and A2B receptor (A2BR) present in an adenosine-rich tumor microenvironment have suppressed effector functions, such as proinflammatory cytokine release, antigen presentation, and Others, making them inert to Cancer cells. Simultaneous blockade of the downstream effects mediated by both receptor subtypes with a dual inhibitor has the potential to reverse adenosine-mediated suppression of tumor immune surveillance as either a single-agent treatment or in combination with Other immunotherapy agents such as anti-PD-1/PD-L1 monoclonal antibodies. This publication describes the discovery and optimization of a novel series of potent and selective dual A2AR/A2BR antagonists, resulting in compound 46 (MK-1088) being identified for progression to human clinical studies.

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