2. Academic Validation
  3. Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer

Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer

  • J Med Chem. 2023 Dec 14;66(23):15776-15800. doi: 10.1021/acs.jmedchem.3c01271.
Rebecca Boutin 1,  Hiu-Fung Lee 1,  Tian Lai Guan 1 2,  Tan Trieu Nguyen 3,  Xian Fang Huang 3,  Daniel D Waller 4,  Jordan Lu 5,  Iok In Christine Chio 5 6,  René P Michel 7,  Michael Sebag 3 8,  Youla S Tsantrizos 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, McGill University, Montreal, Québec H3A 0B8, Canada.
  • 2 Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada.
  • 3 Department of Medicine, McGill University, Montreal, Québec H3A 1A1, Canada.
  • 4 Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, British Columbia V5Z 1L3, Canada.
  • 5 Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 6 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 7 Department of Pathology, McGill University, Montréal, Québec H3A 1A1, Canada.
  • 8 Division of Hematology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada.
PMID: 37982711 DOI: 10.1021/acs.jmedchem.3c01271
Abstract

Novel C6-substituted pyrazolo[3,4-d]pyrimidine- and C2-substituted purine-based bisphosphonate (C6-PyraP-BP and C2-Pur-BP, respectively) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) were designed and evaluated for their ability to block the proliferation of multiple myeloma (MM), pancreatic ductal adenocarcinoma (PDAC), and colorectal Cancer (CRC) cells. Pyrazolo[3,4-d]pyrimidine analogs were identified that induce selective intracellular target engagement leading to Apoptosis and downregulate the prenylation of Rap-1A in MM, PDAC, and CRC cells. The C6-PyraP-BP inhibitor RB-07-16 was found to exhibit antitumor efficacy in xenograft mouse models of MM and PDAC, significantly reducing tumor growth without substantially increasing liver Enzymes or causing significant histopathologic damage, usually associated with hepatotoxicity. RB-07-16 is a metabolically stable compound in cross-species liver microsomes, does not inhibit key CYP 450 Enzymes, and exhibits good systemic circulation in rat. Collectively, the current studies provide encouraging support for further optimization of the pyrazolo[3,4-d]pyrimidine-based GGPPS inhibitors as potential human therapeutics for various cancers.

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