5ZQQ
Tankyrase-2 in complex with compound 52
Summary for 5ZQQ
| Entry DOI | 10.2210/pdb5zqq/pdb |
| Descriptor | Tankyrase-2, ZINC ION, 1-methyl-1'-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)spiro[indole-3,4'-piperidin]-2(1H)-one, ... (7 entities in total) |
| Functional Keywords | tankyrase, parp, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 25131.57 |
| Authors | Niwa, H.,Shirai, F.,Sato, S.,Yoshimoto, N.,Tsumura, T.,Okue, M.,Shirouzu, M.,Seimiya, H.,Umehara, T. (deposition date: 2018-04-19, release date: 2019-04-03, Last modification date: 2023-11-22) |
| Primary citation | Shirai, F.,Tsumura, T.,Yashiroda, Y.,Yuki, H.,Niwa, H.,Sato, S.,Chikada, T.,Koda, Y.,Washizuka, K.,Yoshimoto, N.,Abe, M.,Onuki, T.,Mazaki, Y.,Hirama, C.,Fukami, T.,Watanabe, H.,Honma, T.,Umehara, T.,Shirouzu, M.,Okue, M.,Kano, Y.,Watanabe, T.,Kitamura, K.,Shitara, E.,Muramatsu, Y.,Yoshida, H.,Mizutani, A.,Seimiya, H.,Yoshida, M.,Koyama, H. Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors. J. Med. Chem., 62:3407-3427, 2019 Cited by PubMed Abstract: The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents. PubMed: 30883102DOI: 10.1021/acs.jmedchem.8b01888 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.29 Å) |
Structure validation
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