JH-RE-06 JH-RE-06 is a potent REV1-REV7 interface inhibitor with an IC50 of 0.78 μM and Kd value of 0.42 μM, disrupting REV1-POL ζ-mediated mutagenic translesion synthesis (TLS).
JH-RE-06 disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced-toxicity in cultured human and mouse cell lines.
In vivo
JH-RE-06 improves tumor cell response to cisplatin in vivo. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.