Biomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach

Abstract

Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against human thymidylate synthase (hTS) relative to mouse TS which is not predicted to adopt an inactive conformer. The current research aims to identify novel, lead inhibitors of hTS and examine the prediction that they bind selectively to hTS enzymes existing in different conformational equilibria. Conformer-selectivity was evaluated through performing activity inhibition studies, as well as intrinsic fluorescence (IF) studies in comparison to the known orthosteric inhibitor raltitrexed (RTX). Human TS was isolated from recombinant bacteria expressing either native hTS, capable of conformational switching, or an actively stabilized mutant (R163K-hTS). The examined test compounds were rationally or virtually predicted to have inhibitory activity against hTS. Among these compounds, glutarate, N-(4-carboxyphenyl) succinamic acid, and diglycolic anhydride showed higher selectivity towards native hTS as compared to R163K-hTS. The active site inhibitor RTX showed significantly higher inhibition of R163K-hTS relative to hTS. Targeting hTS via conformational selectivity represents a future approach for overcoming reported resistance towards active-state TS analogs.

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

“…Compounds which are structural analogues of thymidylate synthase substrates, such as 5-fluorouracil, combine with TS to form inactive complexes. This leads to the depletion of thymidylic acid in the cells, which results in the inhibition of their division and ultimately death [59,60]. DNA synthesis in cancer cells is higher than in normal cells; therefore, thymidylate synthase inhibitors constitute an important group of anti-cancer drugs.…”

Efficacy and safety of raltitrexed‐based transcatheter arterial chemoembolization for intermediate and advanced hepatocellular carcinoma: A multicenter real‐world study

“…13,14 Some studies have shown that raltitrexed has antitumor effects on a variety of cancers. [14][15][16] Recently, a prospective study has shown that raltitrexed plus oxaliplatin-based TACE could be effective with few adverse reactions in the treatment of unresectable HCC. 17 Each patient completed the informed consent form for TACE.…”

Acetaminophen-trace Pharmaceutical Bioremediation using Two Isolated Novel Environment-Friendly Phenotypically/Genotypically-characterized Streptomyces Strains; Chemo-informatics & Experimentally tested for Cytotoxicity & Biological Activity

“…Limitations. The exact mechanism of the novel bacterial strains biological activity to be characterized and more characterization(s) if they could prove chemotherapeutic effects (El-Mesallamy et al, 2018) based on the bio-degradation products predicted downstream target enzymes or membrane proteins/receptors.…”