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

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 myelo...

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Published in:	Journal of medicinal chemistry Vol. 66; no. 23; pp. 15776 - 15800
Main Authors:	Boutin, Rebecca, Lee, Hiu-Fung, Guan, Tian Lai, Nguyen, Tan Trieu, Huang, Xian Fang, Waller, Daniel D., Lu, Jordan, Christine Chio, Iok In, Michel, René P., Sebag, Michael, Tsantrizos, Youla S.
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 14-12-2023
Subjects:	Animals Apoptosis Carcinoma, Pancreatic Ductal Cell Line, Tumor Cell Proliferation Colorectal Neoplasms - drug therapy Diphosphonates - pharmacology Diphosphonates - therapeutic use Geranylgeranyl-Diphosphate Geranylgeranyltransferase Humans Mice Multiple Myeloma Pancreatic Neoplasms - pathology Pyrimidines - pharmacology Pyrimidines - therapeutic use Rats Xenograft Model Antitumor Assays
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Y.S.T. conceptualized and coordinated this project and wrote the manuscript; R.B., H.-F.L., M.S., D.D.W, I.I.C., R.P.M. participated in the editing of the final manuscript; M.S. coordinated the hematology, cellular, and in vivo studies. R.B. and H.-F.L synthesized the inhibitors; T.L.G. performed the in vitro inhibition assays; D.D.W. guided the cell-based assays and the CRISPR spCas9-mediated knockout studies for GGPS1 and FDPS and evaluated the SD of the results observed in the in vivo study in the xenograft PDAC (MIA PaCa-2) model; T.T.N. and T.L.G. performed the cell-based assays; D.D.W. and X.F.H. performed and analyzed the in vivo efficacy studies; I.I.C and J.L. performed and wrote the section on the PDAC organoids; and R.P.M. coordinated the processing of the livers for histopathology, performed the grading of the putative histopathologic findings, and wrote the related sections of the manuscript. Author Contributions
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.3c01271