Development of poly(ADP-ribose) glycohydrolase inhibitors and tetracyclic indoles as anticancer compounds
type: CreativeWork
description: In the quest for novel anticancer small molecules, one of two major complementary strategies, either a target- or phenotype-based approach, is generally utilized. Target-based approaches, in which targets are first identified based on their cellular function and an inhibitor is subsequently developed, are effective in some areas, but are not universally successful. Phenotype-based approaches have consistently lead to the discovery of successful drugs and with recent improvements in target-identification methods, these approaches are regaining popularity. Described herein is the target-based development of poly(ADP-ribose) glycohydrolase (PARG) inhibitors as putative anticancer compounds as well as the discovery of a class of potent anticancer tetracyclic indoles through a phenotypic screen. PARG plays a crucial role in DNA damage repair, and lack of PARG activity after DNA damage prevents repair and causes a build-up of toxic PAR chains. As such, PARG inhibitors have been pursued for decades as anticancer compounds. In this document, the structure-activity relationship of the rhodanine-based PARG inhibitors (RBPIs) is investigated. Additionally, the RBPIs were found to be specific inhibitors of PARG over both related and unrelated proteins and demonstrated significant activity in cellular lysate. Due to their lack of activity in whole cells, computational lead hopping searches and docking screens were conducted on virtual compound libraries to identify structures that could serve as cell-permeable PARG inhibitors. In a phenotype-based approach, the tetracyclic indole 1257, was identified as a new anticancer compound via a high-throughput screen for cancer cell death. This compound’s activity was characterized with respect to its potency, speed of induced cell death, Hill slope value, Emax value, and type of cell death induced. The activity of 1257 was determined to depend upon early induction of endoplasmic reticulum stress leading to caspase-independent cell death.
abstract: In the quest for novel anticancer small molecules, one of two major complementary strategies, either a target- or phenotype-based approach, is generally utilized. Target-based approaches, in which targets are first identified based on their cellular function and an inhibitor is subsequently developed, are effective in some areas, but are not universally successful. Phenotype-based approaches have consistently lead to the discovery of successful drugs and with recent improvements in target-identification methods, these approaches are regaining popularity. Described herein is the target-based development of poly(ADP-ribose) glycohydrolase (PARG) inhibitors as putative anticancer compounds as well as the discovery of a class of potent anticancer tetracyclic indoles through a phenotypic screen. PARG plays a crucial role in DNA damage repair, and lack of PARG activity after DNA damage prevents repair and causes a build-up of toxic PAR chains. As such, PARG inhibitors have been pursued for decades as anticancer compounds. In this document, the structure-activity relationship of the rhodanine-based PARG inhibitors (RBPIs) is investigated. Additionally, the RBPIs were found to be specific inhibitors of PARG over both related and unrelated proteins and demonstrated significant activity in cellular lysate. Due to their lack of activity in whole cells, computational lead hopping searches and docking screens were conducted on virtual compound libraries to identify structures that could serve as cell-permeable PARG inhibitors. In a phenotype-based approach, the tetracyclic indole 1257, was identified as a new anticancer compound via a high-throughput screen for cancer cell death. This compound’s activity was characterized with respect to its potency, speed of induced cell death, Hill slope value, Emax value, and type of cell death induced. The activity of 1257 was determined to depend upon early induction of endoplasmic reticulum stress leading to caspase-independent cell death.
author: Knezevic, Claire
language: en
keywords: anticancer, poly(ADP-ribose) glycohydrolase (PARG), endoplasmic reticulum (ER) stress, lead hopping, phenotypic screen
date published: 2014-09-16T17:17:26Z
date modified: 2026-07-22T22:25:40Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/50439