2. Academic Validation
  3. Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase

Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase

  • J Med Chem. 2022 Feb 10;65(3):2471-2496. doi: 10.1021/acs.jmedchem.1c01913.
Hiu-Fung Lee 1,  Cyrus M Lacbay 1,  Rebecca Boutin 1,  Alexios N Matralis 1,  Jaeok Park 1 2,  Daniel D Waller 3 4,  Tian Lai Guan 1,  Michael Sebag 3 4,  Youla S Tsantrizos 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada.
  • 2 Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
  • 3 Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada.
  • 4 Division of Hematology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada.
PMID: 35077178 DOI: 10.1021/acs.jmedchem.1c01913
Abstract

Novel analogues of C-2-substituted thienopyrimidine-based bisphosphonates (C2-ThP-BPs) are described that are potent inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class of compounds induce target-selective Apoptosis of multiple myeloma (MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety that connects their (((2-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methylene)bisphosphonic acid core to various side chains. The structural diversity of this linker moiety, as well as the side chains attached to it, was investigated and found to significantly impact the toxicity of these compounds in MM cells. The most potent inhibitor identified was evaluated in mouse and rat for liver toxicity and systemic exposure, respectively, providing further optimism for the potential value of such compounds as human therapeutics.

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