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

Hiu-Fung Lee; Cyrus M Lacbay; Rebecca Boutin; Alexios N Matralis; Jaeok Park; Daniel D Waller; Tian Lai Guan; Michael Sebag; Youla S Tsantrizos

doi:10.1021/acs.jmedchem.1c01913

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. Epub 2022 Jan 25.

Authors

Hiu-Fung Lee¹, Cyrus M Lacbay¹, Rebecca Boutin¹, Alexios N Matralis¹, Jaeok Park^{1

2}, Daniel D Waller^{3

4}, Tian Lai Guan¹, Michael Sebag^{3

4}, Youla S Tsantrizos^{1

2}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Antineoplastic Agents / toxicity
Bone Marrow Cells / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / therapeutic use*
Enzyme Inhibitors / toxicity
Female
Fungal Proteins / antagonists & inhibitors
Fungal Proteins / metabolism
Geranylgeranyl-Diphosphate Geranylgeranyltransferase / antagonists & inhibitors*
Geranylgeranyl-Diphosphate Geranylgeranyltransferase / metabolism
Humans
Liver / drug effects
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Multiple Myeloma / drug therapy*
Protein Binding
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / therapeutic use*
Pyrimidines / toxicity
Rats
Saccharomyces cerevisiae / enzymology
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / metabolism
Thiophenes / therapeutic use*
Thiophenes / toxicity

Substances

Antineoplastic Agents
Enzyme Inhibitors
Fungal Proteins
Pyrimidines
Thiophenes
Geranylgeranyl-Diphosphate Geranylgeranyltransferase

Grants and funding

CIHR/Canada