Inhibitors of guanosine monophosphate synthetase as therapeutic agents

Inventors

Zhang, Chao • Ni, Feng • EKANAYAKE, Arunika • Espinosa, Biancha

Assignees

University of Southern California USC

Abstract

The invention provides a series of GMPS enzyme inhibitors. The invention includes potent GMPS inhibitors that specifically and covalently bind to GMPS, exhibit broad anti-cancer activity, block the infection efficiency of viruses, and have the potentials to suppress undesired immune responses. These novel inhibitors of GMPS, and their derivatives, have tremendous potentials to be used as therapeutic agents for the treatment of cancers, viral infection and immune disorders.

Core Innovation

The disclosed subject matter relates to novel small-molecule inhibitors of guanosine monophosphate synthetase (GMPS) for therapeutic use. The document describes GMPS-targeting compound scaffolds in Formulas I and II with variable substituents, and exemplified compounds 1–5. The compounds are described as inhibiting GMPS and as having covalent binding to GMPS in live-cell studies.

The problem described is the need for therapeutics that inhibit GMPS, including therapeutic uses involving cancer, viral infection, immune-response suppression, autoimmune/inflammatory disorders, and organ and tissue transplant contexts. The disclosure frames GMPS as a target and provides GMPS inhibitor compounds designed around Formulas I and II, with variable groups denoted by X (X = N or CH) and substituents R1 and R2.

The disclosure supports GMPS inhibition using recombinant human GMPS inhibition data reported in nanomolar ranges, and it highlights differences in inhibition potency among compounds 1–5. It further indicates structure–activity relationship findings that a chloroacetamide group is essential for covalent labeling. Live-cell covalent labeling is reported with dose-dependent low-nanomolar covalent labeling and LC/MS/MS confirmation of a ~75 kDa GMPS band.

Claims Coverage

The independent claim covers a GMPS inhibitor compound selected from a depicted group, including optically pure stereoisomers and pharmaceutically acceptable salts. The claim set includes refinement in dependent claims that specify particular depicted compound structures and salt forms, and that cover pharmaceutical compositions comprising the selected compound and a pharmaceutically acceptable carrier.

Across the independent and dependent claims, coverage centers on a compound selected from depicted GMPS inhibitor structures, including optically pure stereoisomers and pharmaceutically acceptable salts, and pharmaceutical compositions that include those selected compounds with a pharmaceutically acceptable carrier.

Stated Advantages

Documented Applications