6A84

Tankyrase-2 in complex with compound 15d

Summary for 6A84

• Entry DOI: 10.2210/pdb6a84/pdb
• Descriptor: Tankyrase-2, ZINC ION, 2-(4-chloro-1,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, ... (7 entities in total)
• Functional Keywords: tankyrase, parp, adp-ribosylation, transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 25138.01

Authors

Niwa, H.,Shirai, F.,Sato, S.,Yoshimoto, N.,Tsumura, T.,Okue, M.,Shirouzu, M.,Seimiya, H.,Umehara, T. (deposition date: 2018-07-06, 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

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: 30883102
DOI: 10.1021/acs.jmedchem.8b01888

Experimental method

X-RAY DIFFRACTION (1.98 Å)