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The gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) is a ligand-activated nuclear hormone receptor that plays central roles in regulating adipogenesis and maintaining lipid and glucose homeostasis. PPARγ is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. While clinically efficacious, the TZDs exhibit significant side effects that are mechanistically linked to PPARγ including weight gain, edema, and heart failure. SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that are critical for normal PPARγ function and act by repressing PPARγ-mediated transcriptional activity in the absence of agonist ligands. In order to explore an alternate method of activating PPARγ signaling, we designed a biochemical assay for the purpose of high-throughput screening (HTS) to identify inhibitors of the interaction between PPARγ and corepressors from our in-house library compounds (292K), which might act as pharmacological agonists. Herein, we report the use of this method to discover small molecule inhibitors of the corepressor interaction with PPARγ. Following hit validation and evaluation, we identified small molecule inhibitors acting through this novel mechanism that potently induce a cellular response similar to the known PPARγ agonist rosiglitazone. In addition, we also confirmed that our hit compound revealed induced adipogenesis in 3T3-L1 cell and reduced fat storage in C.elegans model. These findings highlight the potential of targeting the interaction of PPARγ and SMRT for the discovery of small molecule agonists of PPARγ. Citation Format: Jaeki Min, Ramy Naguib Attia, Leggy A Arnold, Kelly Teske, Michele Connelly, George Lemieux, Kaveh Ashrafi, Anang Shelat, R. Kiplin Guy. Discovery of small molecule inhibitors of the interaction between PPARγ and SMRT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5389. doi:10.1158/1538-7445.AM2014-5389