Related Experiment Video
Updated: Nov 27, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Identification of an irreversible PPARγ antagonist with potent anticancer activity
Youyi Peng1, Qiang Zhang2, Robert M Zielinski3
1Biomedical Informatics Shared Resource, Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Abstract:
Melanoma is responsible for most skin cancer deaths, and its incidence continues to rise year after year. Different treatment options have been developed for melanoma depending on the stage of the disease. Despite recent advances in immuno- and targeted therapies, advanced melanoma remains incurable and thus an urgent need persists for safe and more effective melanoma therapeutics. In this study, we demonstrate that a novel compound MM902 (3-(3-(bromomethyl)-5-(4-(tert-butyl) phenyl)-1H-1,2,4-triazol-1-yl) phenol) exhibited potent efficacies in inhibiting the growth of different cancer cells, and suppressed tumor growth in a mouse xenograft model of malignant melanoma. Beginning with MM902 instead of specific targets, computational similarity- and docking-based approaches were conducted to search for known anticancer drugs whose structural features match MM902 and whose pharmacological target would accommodate an irreversible inhibitor. Peroxisome proliferator-activated receptor (PPAR) was computationally identified as one of the pharmacological targets and confirmed by in vitro biochemical assays. MM902 was shown to bind to PPARγ in an irreversible mode of action and to function as a selective antagonist for PPARγ over PPARα and PPARδ. It is hoped that MM902 will serve as a valuable research probe to study the functions of PPARγ in tumorigenesis and other pathological processes.
Insights
A novel compound, MM902, effectively inhibited melanoma growth in preclinical models. MM902 acts as a selective irreversible antagonist of peroxisome proliferator-activated receptor gamma (PPARγ), offering a potential new therapeutic avenue for melanoma.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Melanoma is a deadly skin cancer with rising incidence and limited treatment options for advanced stages.
- Current therapies, including immunotherapy and targeted treatments, show limitations, highlighting the need for novel therapeutics.
- MM902, a new compound, demonstrated significant anti-cancer activity in preliminary studies.
Purpose of the Study:
- To investigate the anti-cancer efficacy of the novel compound MM902.
- To identify the molecular target and mechanism of action of MM902.
- To explore MM902 as a potential therapeutic agent for melanoma.
Main Methods:
- Computational approaches (similarity and docking) were used to identify potential targets for MM902.
- In vitro biochemical assays were performed to confirm target engagement.
- In vivo studies using a mouse xenograft model of malignant melanoma were conducted to assess tumor suppression.
Main Results:
- MM902 demonstrated potent inhibition of various cancer cell growth and suppressed melanoma tumor growth in vivo.
- Peroxisome proliferator-activated receptor (PPAR) was computationally identified as a target of MM902.
- MM902 was confirmed to bind PPARγ irreversibly and act as a selective antagonist over PPARα and PPARδ.
Conclusions:
- MM902 exhibits significant anti-melanoma efficacy through irreversible antagonism of PPARγ.
- This compound represents a promising lead for developing new melanoma therapeutics.
- MM902 can serve as a valuable research tool for studying PPARγ in cancer and other diseases.
More Related Videos
10:51Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
19:44Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
Published on: May 30, 2012
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity