Identification Of A Novel Compound, M02455, That Induces Poly(Adp-Ribose) (Par) Accumulation And Inhibits The Growth Of Cancer Cells In Vitro And In Vivo

Poly (ADP-ribose) chain (PAR) formed by poly (ADP-ribose) polymerase (PARP) is catabolized mainly by poly (ADP-ribose) glycohydrolase (PARG). PARG is emerging as a therapeutic target for cancer, because its inhibition leads to cell death in some kinds of cancer cell lines. In order to obtain small molecules that effectively inhibit PARG protein, an in-house collection of ∼10,000 small molecules were screened for their ability to accumulate the PAR in A549 cells at 5 μM. We identified ∼100 hit compounds. Among them, MO2282 and MO2455 induced the most significant accumulation of PAR. MO2455 is an analogue of MO2282 with improved water-solubility. MO2282 and MO2455 were evaluated in vitro for their ability to inhibit the catalytic activity of PARG. MO2282 and MO2455 showed modest inhibition activities against recombinant rat PARG. They also inhibited the growth of various kinds of cancel cell lines in vitro at an IC50 value of 0.05 - 3.0 μM and showed different spectrum of antitumor activity from conventional anticancer drugs, CDDP, ADM, PTX, and CPT-11. Next, we investigated the growth-inhibitory effect of MO2455 on A549 cells in a xenotransplanted model. A significant anti-tumor activity was observed in mice when treated with MO2455 at doses of 25 mg/kg every two days. Although treatment-related body weight loss was observed in mice treated with MO2455, body weight recovered by day 8. In conclusion, the present data suggest that MO2455 has potential as a cancer drug with different mechanisms of action from conventional anti-cancer drugs. Citation Format: Tatsu Shimoyama, Takeshi Sawada, Mari Akimoto, Yuka Sasaki, Hiroaki Fujimori, Yoshinobu Ishikawa, Tadashi Okawara, Tetsumi Irie, Takeji Takamura, Kenji Matsuno, Kengo Inoue, Mitsuko Masutani, Fumiaki Koizumi. Identification of a novel compound, MO2455, that induces poly(ADP-ribose) (PAR) accumulation and inhibits the growth of cancer cells in vitro and in vivo . [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4808.