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1.
Microbiol Spectr ; 12(1): e0367723, 2024 Jan 11.
Article in English | MEDLINE | ID: mdl-38078724

ABSTRACT

IMPORTANCE: MmpL3 is a protein that is required for the survival of bacteria that cause tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections. This report describes the discovery and characterization of a new small molecule, MSU-43085, that targets MmpL3 and is a potent inhibitor of Mycobacterium tuberculosis (Mtb) and M. abscessus survival. MSU-43085 is shown to be orally bioavailable and efficacious in an acute model of Mtb infection. However, the analog is inactive against Mtb in chronically infected mice. Pharmacokinetic and metabolite identification studies identified in vivo metabolism of MSU-43085, leading to a short half-life in treated mice. These proof-of-concept studies will guide further development of the MSU-43085 series for the treatment of TB or NTM infections.


Subject(s)
Mycobacterium Infections, Nontuberculous , Mycobacterium tuberculosis , Tuberculosis , Animals , Mice , Tuberculosis/drug therapy , Tuberculosis/microbiology , Mycobacterium Infections, Nontuberculous/microbiology , Nontuberculous Mycobacteria
2.
Biomedicines ; 10(5)2022 Apr 19.
Article in English | MEDLINE | ID: mdl-35625675

ABSTRACT

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.

3.
Org Biomol Chem ; 17(10): 2734-2746, 2019 03 06.
Article in English | MEDLINE | ID: mdl-30778435

ABSTRACT

Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic "proteolytic machine" such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.


Subject(s)
Esters/chemistry , Pipecolic Acids/chemistry , Pipecolic Acids/pharmacology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/pharmacology , Catalytic Domain , Drug Design , Inhibitory Concentration 50 , Molecular Docking Simulation , Pipecolic Acids/metabolism , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/metabolism
4.
J Org Chem ; 80(3): 1440-5, 2015 Feb 06.
Article in English | MEDLINE | ID: mdl-25574949

ABSTRACT

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.


Subject(s)
Alkenes/chemistry , Amino Alcohols/chemistry , Amino Alcohols/chemical synthesis , Carbamates/chemistry , Carbamates/chemical synthesis , Oxazolidinones/chemistry , Oxazolidinones/chemical synthesis , Amination , Catalysis , Cyclization , Indicators and Reagents/chemistry , Magnetic Resonance Spectroscopy , Stereoisomerism
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