Isozyme-specific inhibition of GSTP1-1: a crucial element in cancer-targeting drugs

Abstract

Selectively targeting cancer cells has been a main challenge in cancer therapy. The purpose is to spare normal cells and minimize side effects. Targeting the antioxidant enzymes (i.e. GST) for the purpose of selectively killing cancer cells has attracted much attention in the past few decades. The intention of lowering the antioxidant enzymes is “tipping” the ROS concentrations to levels above the cytotoxic threshold. This would result in extensive damage to the cellular macromolecules and organelles leading to cell death. Here we focused on the glutathione S-transferase pi 1 (GSTP1), because it is one of the overexpressed antioxidant enzymes in cancer and has been targeted for the purpose of killing cancer cells. However, most available GSTP1 inhibitors do not show selectivity towards the isozyme. This can potentially lead to many side effects. Therefore, the search for optimal selective GSTP1 inhibitors is still underway. The novelty of this review stems from highlighting the significance of selectively targeting GSTP1. We also addressed the structural feature of the enzyme which challenges the design of novel selective GSTP1 inhibitors. We then provide guidelines to help resolve these challenges to help design future compounds. The first objective of this review is to present a brief literature review to highlight the importance of selectively targeting GSTP1. Briefly, the lack of selectivity towards GSTP1 has resulted in extensive side effects which limited reaching advanced clinical trials. We screened publications on many potential inhibitors, including some that reached phase I and II clinical trials, for their ability to bind with GSTP1, GSTM, and GSTA. All compounds appear to bind different GST isozymes (at least to some extent). The second objective is to present differences in the structures of GST isotypes (GSTP1, GSTM, GSTA) which could allow selectively targeting a certain isotype. Our modelling results highlight the importance of certain structural moieties for better selective binding to GSTP1.