Abstract 3106: Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma

Abstract

Abstract Hepatocellular Carcinoma (HCC) is the leading form of liver cancer, the 6th most common type, and the 4th leading cause of cancer death worldwide. Interestingly, HCC occurs two to four times more in males than females. A possible explanation for this sexual dimorphism is the implication of androgen and the Androgen Receptor (AR). However, previous clinical trials among HCC patients have shown no significant survival benefit after the administration of antiandrogen drugs (e.g. Enzalutamide) that block the Ligand-Binding Domain (LBD) of the Full-length Androgen Receptor (AR-FL). Instead, our lab has developed a novel approach using small molecular analogs of the previously FDA-approved drug, Niclosamide, to degrade full-length AR and its spliced variants within HCC cell lines. The primary goal of this project was to evaluate the minimal necessary pharmacophores for the biological activity of the Niclosamide scaffold. To do so, 23 analogs were synthesized and tested on three different HCC cell lines (SNU 475, 423, and LM3) using a CCK8 cell viability assay. Preliminary results have shown that only Niclosamide analogs with i.) electron-withdrawing groups on the aniline ring; ii) a conserved hydroxy group on the salicylic ring, and iii) a free amide group in the middle have cytotoxic activity. Further work will be completed using western blot to determine if there’s any correlation between androgen receptor degradation and in vitro potency. In conclusion, Niclosamide analogs have indicated promising potential to inhibit HCC cell lines by targeting the Androgen Receptor. Citation Format: Jeffrey Cheng, Enming Xing, Shabber Mohammed, Emma Montgomery, Lauren Granchie, Christopher Coss, Pui-Kai Li. Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3106.