2. Academic Validation
  3. Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α

Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α

  • J Med Chem. 2022 Aug 11;65(15):10318-10340. doi: 10.1021/acs.jmedchem.1c02109.
Victor W Mak 1,  Akash M Patel 1,  Rose Yen 1,  Jennifer Hanisak 2,  Yeon-Hee Lim 1,  Jianming Bao 1 3,  Rong Zheng 4,  W Michael Seganish 1,  Yang Yu 2,  David R Healy 5,  Aimie Ogawa 6,  Zhao Ren 6,  Aileen Soriano 7,  Grigori P Ermakov 8,  Maribel Beaumont 8,  Essam Metwally 9,  Alan C Cheng 9,  Andreas Verras 10 11,  Thierry Fischmann 11,  Matthias Zebisch 12,  H Leonardo Silvestre 12,  Paul A McEwan 12,  John Barker 12,  Paul Rearden 13 14,  Thomas J Greshock 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 2 Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 3 Ionova Life Science, Shenzhen 518122, Guangdong, China.
  • 4 IDSU, Wuxi AppTec Co., Ltd, Shanghai 200131, China.
  • 5 Discovery Biology, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 6 Quantitative Biosciences, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 7 Mass Spectrometry and Biophysics, Computation and Structural Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 8 PPDM Discovery Bioanalytics, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 9 Computational and Structural Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
  • 10 Schrodinger Inc., 120 West 45th Street, 17th Floor, New York, New York 10036-4041, United States.
  • 11 Computational and Structural Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 12 Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • 13 DMPK, Recursion Pharmaceuticals, Salt Lake City, Utah 84101, United States.
  • 14 PPDM, Merck & Co., Inc., South San Francisco, California 94080, United States.
PMID: 35878399 DOI: 10.1021/acs.jmedchem.1c02109
Abstract

Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic Peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate in vitro phosphorylation of vasodilator-stimulated phosphoprotein as well as antiproliferative effects in human pulmonary arterial smooth muscle cells. Hydrogen/deuterium exchange mass spectrometry experiments with the small molecule activators revealed a mechanism of action consistent with cGMP-induced activation, and an X-ray co-crystal structure with a construct encompassing the regulatory domains illustrated a binding mode in an allosteric pocket proximal to the low-affinity cyclic nucleotide-binding domain.

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