A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

Quinazoline and its derivatives have drawn much attention
in the
development of potential antitumor agents. Here, we synthesized a
series of 1,2,3-triazole derivatives of quinazoline at the C6 position
and evaluated for their cytotoxic activity in various human cancer
cell lines. We found that compound 5a was the most cytotoxic
to HCT-116 cells (IC50, 0.36 μM). Target profiling
found that 5a directly binds to both the autophagy-associated
protein SQSTM1/P62 and the E3 ligase RNF168, promoting their interaction.
Consistently, 5a treatment induces a decrease in RNF168-mediated
H2A ubiquitination and compromises homologous recombination-mediated
DNA repair, thus increasing the sensitivity of HCT-116 to X-ray radiation.
Moreover, 5a suppressed xenografted tumor growth in mice
in a dose-dependent manner. Taken together, the 1,2,3-triazole derivative
of quinazoline 5a may serve as a novel compound for tumor
therapy based on its role in promoting a P62/RNF168 interaction.