Synthesis, Biological Evaluation, and Structure–Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors

Abstract

APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for ≥95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anti-cancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity has been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogs exhibit single-digit µM activity against the purified APE1 enzyme, comparable activity in HeLa whole cell extract assays, and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice.

Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

“…The inhibitor prevents cleavage of the backbone, whereas APE1 binding is not strongly impacted ( Fig. 3C) (14). In these studies, Rluc expression increased up to >30-fold with a dose-response in the inhibitor concentration for the F-containing plasmid, whereas the WT plasmid remained the same throughout the titration (Fig.…”

Human Apurinic/Apyrimidinic Endonuclease 1

“…The ''low affinity'' attribute may stem from the fact that small molecules are unable to replicate the ''high affinity'' binding contacts seen in the APE1/AP-DNA complex, which spans roughly 7-8 bp in length. Indeed, in an extensive structure-function activity relationship study, the introduced modifications only slightly increased the effectiveness of the analogs against (7,131,142,167), confirming that the nuclease function(s) of the protein plays a critical role in repairing alkylative DNA damage, presumably abasic sites. Future studies will need to examine the utility of the most promising compounds in both combinatorial and synthetic lethal treatment paradigms, and may need to employ covalently linked, small molecules that bind simultaneously multiple functional sites of APE1.…”

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

“…APE1 inhibitors, for example, are currently in development and may have therapeutic application in the near future. [34,97,98]. Moreover, DNA polymerase beta inhibitor is also currently under developmental stage and early reports reveal the ability of DNA pol β inhibitors to potentiate the cytotoxicity of alkylating agents [99].…”