Abstract 4479: Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate

Abstract

Abstract The anthelmintic drug, Niclosamide, has a multitude of promising anticancer properties including inhibition of key signaling pathways involved in tumorigenesis, disruption of mitochondrial function, degradation of the overexpressed androgen receptor, and more. However, a key limitation of the clinical use of Niclosamide in cancer treatment is its low solubility and cellular uptake, which result in poor pharmacokinetic properties and dose-limiting GI toxicities at concentrations lower than the therapeutic threshold of the drug. To overcome this, we hypothesized that we could use amino acid conjugated niclosamide prodrugs to improve cellular uptake by creating a substrate of the PepT1 transport protein. The overexpression of the PepT1 transport protein that is involved in many hormonal cancers is being used to our advantage. Our study involved first synthesizing a group of niclosamide and niclosamide analogs conjugated with polar or nonpolar amino acids. Next, we conducted a Glycine-Sarcosine assay measuring changes in the uptake of the dipeptide glycyl-sarcosine (Gly-Sar). Our initial step was to examine if our conjugates could disrupt the absorption of Gly-Sar. The active conjugate will be tested whether they are substrates or inhibitors of the transporter. For the future, we have plans to determine the half-maximal inhibitory concentration (IC50) of niclosamide conjugates in various cancer cell lines and to quantify cleavage of the prodrugs intracellularly. Citation Format: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia. Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4479.