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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