Antitumor agent-81

Antitumor agent-81 (compound 5a) is a low cytotoxicity P62-RNF168 agonist that enhances the interaction between P62 and RNF168. Antitumor agent-81 induces a reduction in H2A ubiquitination mediated by RNF168 and impairs homologous recombination-mediated DNA repair. Antitumor agent-81 also inhibits the growth of xenograft tumors in mice in a dose-dependent manner.

Antitumor agent-81 (20 μM, 72 h) has an IC50 of 0.36 μM for the cancer cell line HCT116 and an IC50 of 1.18 μM for A549. It shows cytotoxicity against cancer cells A357, HeLa, HepG2, MCF-7, MDA-MB-231, MGC-803, and H2OS, but does not induce cell apoptosis and has lower toxicity towards normal cells MCF-10A[1].Antitumor agent-81 (1-5 μM; 24 h) affects the HR (homologous recombination)-mediated DSB repair in HCT-116 cells, contributing to its antitumor activity[1].Antitumor agent-81 enhances the interaction between P62 and RNF168 in HCT-116 cells, with a Kd of 20.97 μM[1].Antitumor agent-81 inhibits the catalytic activity of RNF168 and the E3 ligase activity of RNF168 in HCT-116 cells[1].

Antitumor agent-81 (12.5-100 mg/kg, i.p., single dose) has an MTD of 50 mg/kg in BALB/c mice, while in female nude mice, the MTD is 12.5 mg/kg[1].Antitumor agent-81 (5-10 mg/kg, i.p., single every 3 days for 22 days) promotes tumor apoptosis and inhibits tumor growth in mice[1].1.19Pharmacokinetic Parameters of Antitumor agent-81 in Female BALB/c nude mice[1].

References:
[1]. Wang FC, et al. A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62. J Med Chem. 2022 Nov 4.