IC50: ML-323 is a highly potent and selective inhibitor of USP1-UAF1 with IC50 value of 76 nM.
ML-323 is an inhibitor of USP1-UAF1 with remarkable selectivity and relatively low cytotoxicity to the human cells. [1] USP1-UAF1 is closely linked to the DNA damage response and is recently suggested as a strategy for overcoming drug resistance during antitumor therapy. [1]
In vitro: Studies in H596 cells showed that ML-323 blocked the deubiquitination of PCNA and FANCD2 via suppressing USP1–UAF1 activity. It was reported that ML-323 potently inhibited USP1-UAF1 with IC50 values of 76 nM and 174 nM in ubiquitin-rhodamine (Ub-Rho) assay and orthogonal gel-based assay, respectively. In addition, by targeting TLS and FA, two major DNA damage response pathways, ML-323 increased cisplatin cytotoxicity both in NSCLC H596 cells and U2OS osteosarcoma cells. Moreover, this agent exhibited a high selectivity to human DUBs, deSUMOylase, deneddylase and unrelated proteases. [1]
In vivo: So far, no in vivo study has been conducted.
Clinical trial: So far, no clinical trial has been conducted.
Reference:
[1]Liang Q, Dexheimer TS, Zhang P, Rosenthal AS, Villamil MA, You C, Zhang Q, Chen J, Ott CA, Sun H, Luci DK, Yuan B, Simeonov A, Jadhav A, Xiao H, Wang Y, Maloney DJ and Zhuang Z. A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses. Nat Chem Biol. 2014 April; 10(4): 298–304.
