Water-soluble SCR7 Can Abrogate DNA End Joining and Induce Cancer Cell Death

Abstract

Small molecule inhibitors targeting DNA repair pathways in cancer cells is a novel and promising approach in cancer therapy, which can improve current therapeutic regimen. Although various attempts have been made for designing inhibitors against DNA damage response and repair proteins, reports on Nonhomologous End Joining (NHEJ) inhibitors are limited. Of the several chemical moieties identified, SCR7 and its oxidized form are novel and potent DNA Ligase IV inhibitors involved in the abrogation of DNA end joining thereby leading to cell death. In the present study, we have synthesized sodium salt of SCR7 to generate a water-soluble version of the molecule, referred to as water-soluble SCR7 (WS-SCR7). WS-SCR7 inhibits NHEJ in Ligase IV dependent manner, with a subtle effect on Ligase III at higher concentration. No effect on Ligase I mediated joining was observed. WS-SCR7 shows cytotoxicity in cancer cell lines, leading to induction of apoptosis in a dose-dependent manner.

Identification and characterization of mercaptopyrimidine‐based small molecules as inhibitors of nonhomologous DNA end joining

“…Much advancement has been made in the development of Ligase IV inhibitors. After the initial discovery of L189 as a pan-Ligase inhibitor, SCR7 and its various forms showed potent Ligase IV-dependent effects both in vitro and in vivo [23][24][25]33,34,65]. More recently, a spiro-based derivative of SCR7, SCR130, was identified, which showed up to 22-fold improved IC 50 in cancer cell lines and worked in Ligase IV-dependent manner, leading to accumulation of DSBs inside cells and apoptosis [22].…”

“…Previously, DNA Ligase IV inhibitor, SCR7 showed cytotoxicity in cancer cell lines at 40 lM and higher concentrations [24,25]. Although water-soluble versions of SCR7 and pyrazine were synthesized, not much improvement in the IC 50 value was observed [33,34]. Recently, spiro derivatives of SCR7, SCR130 showed up to 22-fold improved IC 50 in cancer cell lines in a Ligase IV-dependent manner [22].…”

“…However, attempts to improve the bioavailability of SCR7 by pluoronic copolymer encapsulation exhibited limited outcomes [30][31][32]. Furthermore, water-soluble sodium salts of SCR7 and SCR7-Pyrazine (Na-SCR7-P) exhibited high IC 50 and inhibited end joining of all three DNA Ligases [33,34]. Another derivative of SCR7, the spirobased SCR130, showed Ligase IV-specificity with > 22fold better cytotoxicity than SCR7 with the accumulation of DNA breaks inside cells [22].…”

SCR7, a potent cancer therapeutic agent and a biochemical inhibitor of nonhomologous DNA end‐joining

“…34,35 SCR7 and its pyrazine form were further developed as water-soluble versions that regressed tumors in mice. [36][37][38] However, water-soluble SCR7 was Ligase IV specific, whereas water-soluble SCR7-pyrazine had pan-ligase activity. 6,36,37 One of the drawbacks of SCR7 is its high IC 50 in cancer cells.…”

“…[36][37][38] However, water-soluble SCR7 was Ligase IV specific, whereas water-soluble SCR7-pyrazine had pan-ligase activity. 6,36,37 One of the drawbacks of SCR7 is its high IC 50 in cancer cells.…”