Discovery and characterization of novel STAT3 and androgen receptor inhibitors in prostate cancer cells
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Prostate cancer (PCa) recurs and leads to incurable castration-resistant prostate cancer (CRPC) after the failure of androgen deprivation therapies (ADT). CRPC development relies on androgen receptor (AR) signalling. The IL-6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL-6/STAT3 and the AR pathway provides opportunities to explore next-generation agents to treat PCa. In a drug discovery and development program, we have screened nearly 600 natural compounds for STAT3 inhibiting activity. In Paper I, we identified the small molecular compound 154 that exhibited dual effects on IL-6/STAT3 and AR pathways. We show here that compound 154 inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and down-regulates the mRNA levels of AR target genes. Compound 154 also inhibits the protein expression of AR and AR splice variants (ARv567es and AR-V7), without altering AR mRNA levels. Compound 154 binds to AR directly, but not to STAT3 and is identified as an antagonist of the AR amino-terminal domain (NTD) by disrupting protein-protein interactions between STAT3 and the AR NTD. Moreover, compound 154 does not reduce AR nuclear translocation. Thus, compound 154 possesses the potential to become a leading compound in novel therapies against CRPC. In Paper II, two small molecules 323-1 and 323-2 were identified in screening and investigated as modulators of the IL-6/STAT3 pathway, which 1) reduce STAT3 transcriptional activity; 2) inhibit phosphorylated STAT3 on Tyr705; 3) disrupt the STAT3 dimerization by directly targeting the SH2 domain of STAT3; 4) inhibit several kinases, including JAK3, TYK1, and FRAP1, in an expanded in vitro kinase screening. Thus, the compounds 323-1and 323-2 are promising leading compounds for cancer treatment. Together, our lab has identified two potential STAT3 SH2 domain inhibitors and one dual AR/STAT3 inhibitor as new leading compounds.
Paper I: Hua, Y., Azeem, W., Shen, Y., Zhang, S., Olsen, J.R., Oyan, A.M., Ke, X., Zhang, W., Kalland, K.H., 2018. Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino-terminal domain. Pharmacol Res Perspect 6 (6), e00437. The article is available in the main thesis. The article is also available at: https://doi.org/10.1002/prp2.437Paper II: Hua, Y., Yuan X., Shen, Y., Azeem, W., Zhang, S., Oyan, A.M., Ke, X., Zhang, W., Kalland, K.H., Novel STAT3 inhibitors targeting STAT3 dimerization by binding to STAT3 SH2 domain. The article is not available in BORA.
PublisherThe University of Bergen
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