Abstract 4487: Simple modifications of 3-HPT for improved in-vivo activtiy

Abstract

Abstract One of the key targets in the treatment of castration resistant prostate cancer is HDAC6. HDAC6 removes acetyl groups from Heat shock protein 90 (HSP90), which is a protein chaperone that folds the androgen receptor. By inhibiting HDAC6 it is possible to prevent the expression of mutated androgen receptors, that are no longer responsive to androgen deprivation therapy, treating castration resistant prostate cancer. The Oyelere lab has previously demonstrated that 3-Hydroxypyridin-2-thione (3-HPT) can serve as a scaffold for HDAC6 inhibitors. While the unaltered 3-HPT has been shown on its own to inhibit HDAC6 in enzyme specific assays. The unaltered 3-HPT had no effect in whole cell assays. This work investigated simple modification of the 3-HPT scaffold to improve the in-vivo activity of 3-HPT. This work is an extension of work previously done in the Oyelere lab. The aim of this work is to apply simple modifications to the 3-HPT scaffold to improve the in-vitro activity. Previously 3-HPT was shown on its own to inhibit HDAC6 with an IC50 of 681nM but have no effect on cell assays. The hypothesis was that by converting the secondary amine into a tertiary amine the pharmacokinetic-properties of 3-HPT allowing can be improved focusing on cellular entry. The specific modification was the addition of alkanes and fluorinated alkanes at the secondary amine. This addition should improve the charge of the compounds improving the invitro activity. Based on molecular docking studies using Autodock vina, the introduction of fluorines improves the binding to HDAC6 by interacting with a hydrophilic pocket near the zinc ion. The preliminary in-vivo results in LnCAP and DU145 cells demonstrate that the addition of fluorinated alkanes has substantially improved the IC50 compared to the base 3-HPT compound. The base 3-HPT compound has an IC50 of greater than 100µM while the compounds with fluorinated alkanes have IC50 values in the range of 2-15µM. this data indicates improved drug likeness. Preliminary IC50 values of compounds in prostate cancer cell lines Compound Name LNCaPIC50 (µM) DU145IC50 (µM) Vero IC50 (µM) SH-1-78 >100 >100 >100 SH-1-94 2.50 19.29 22.53 RK-1-187 96.95 95.45 88.57 SH-1-110 1.27 21.47 17.41 RK-2-16 2.09 62.86 18.76 RK-2-17 >100 >100 >100 RK-2-64 78.36 >100 76.45 RK-2-67 14.19 26.95 11.38 Citation Format: Ryan E. Kern, Susanna Huang, Uche Arunsi, Adegboyega Oyelere. Simple modifications of 3-HPT for improved in-vivo activtiy [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 4487.