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Identification of Small Molecule Inhibitors Targeting COUP-TFII


Prostate cancer is the second most common cancer affecting males in the United States. Hormone therapy has been widely used for prostate cancer treatment, such as androgen deprivation and targeting androgen receptor with small molecules. However, under long-term treatment, patients develop castration-resistant prostate cancer (CRPC) and eventually die. Therefore, it’s urgent to discover novel therapeutic targets to improve prostate cancer treatment. In 2013, the Tsai group identified that COUP-TFII, an orphan nuclear receptor whose overexpression involving in multiple diseases, can serve as a potential drug target for prostate cancer. Recently, the Tsai group further developed novel small molecule inhibitors, CIA1 and CIA2, directly targeting COUPTF-II for prostate cancer treatment.

CIA1 and CIA2 were obtained through a high-throughput screening. They are specific inhibitors targeting COUP-TFII: i) The inhibitors reduce the prostate cell growth while having little effect on cells lacking COUP-TFII. Ii) CIA1 and CIA2 can inhibit the COUP-TFII-activated gene expression and promote the COUP-TFII-repressed gene expression, which were not observed when COUP-TFII was silenced. iii) An RNA-seq analysis showed the similar genome-wide expression profiling of COUP-TFII target genes comparing the CIA1 treated group and the COUP-TFII knockdown group.

A cellular thermal shift assay (CETSA) and biotin-streptavidin pulldown study were performed to further verify that the inhibitors directly interact with COUP-TFII. Furthermore, either W249A or F253A mutation in the ligand binding domain (LBD) can substantially decrease the potency of these inhibitors, demonstrating CIA1 and CIA2 directly bind to COUP-TFII through the ligand binding pocket. Additionally, these inhibitors showed unappreciable binding affinities to other nuclear receptors sharing similar structures based on a pulldown assay, indicating the specificity of these COUP-TFII inhibitors.


Moreover, the inhibitors showed considerable inhibition activity in various prostate cancer cells while barely affecting normal prostate cells. For the in vivo activities, the inhibitors are capable of inducing significant tumor growth inhibition in both xenograft and PDX models without appreciable toxicity in mice. Particularly, not limited to the AR-sensitive tumors, the inhibitors showed good tumor growth inhibition in AR-negative, ARv7-dependent, and AR-null models. This provides a broad potential clinical application in the future.

Previous studies have demonstrated that COUP-TFII can regulate gene expression by recruiting other transcription regulators. Indeed, some transcription regulators interacting with COUP-TFII were impaired after CIA1 treatment. Only FOXA1 knockdown showed the inhibition of prostate cancer cell growth, indicating that COUP-TFII maybe recruit FOXA1 to regulate gene expression and promote prostate cancer cell growth. Further comprehensive mechanism studies disclosed that CIA1 could disrupt the interaction between COUP-TFII and FOXA1, leading to changes in target gene expression.

Although the PK and potency of the inhibitors still need to be further optimized, this study suggests that targeting COUPTF-II with small molecule inhibitors provides a potential avenue to treat prostate cancer and other diseases caused by overexpression of COUP-TFII.

Reference:
1. Qin, J. et al. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature 493, 236–240 (2013).
2. Wang L. et al. Small-molecule inhibitor targeting orphan nucler receptor COUP-TFII for prostate cancer treatment. Sci. Adv. 2020 DOI: 10.1126/sciadv.aaz8031



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