4W6E

Human Tankyrase 1 with small molecule inhibitor

Summary for 4W6E

• Entry DOI: 10.2210/pdb4w6e/pdb
• Related: 4W5S
• Descriptor: Tankyrase-1, ZINC ION, 2-(4-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-4-methylpyridin-3-yl}phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one, ... (4 entities in total)
• Functional Keywords: tankyrase inhibitor small molecule, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: O95271
• Total number of polymer chains: 1
• Total formula weight: 24748.47

Authors

Kazmirski, S.L.,Johannes, J.,Boriack-Sjodin, P.A.,Howard, T. (deposition date: 2014-08-20, release date: 2015-05-13, Last modification date: 2023-12-27)

Primary citation

Johannes, J.W.,Almeida, L.,Barlaam, B.,Boriack-Sjodin, P.A.,Casella, R.,Croft, R.A.,Dishington, A.P.,Gingipalli, L.,Gu, C.,Hawkins, J.L.,Holmes, J.L.,Howard, T.,Huang, J.,Ioannidis, S.,Kazmirski, S.,Lamb, M.L.,McGuire, T.M.,Moore, J.E.,Ogg, D.,Patel, A.,Pike, K.G.,Pontz, T.,Robb, G.R.,Su, N.,Wang, H.,Wu, X.,Zhang, H.J.,Zhang, Y.,Zheng, X.,Wang, T.
Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology.
Acs Med.Chem.Lett., 6:254-259, 2015

PubMed Abstract: The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.

PubMed: 25815142
DOI: 10.1021/ml5003663

Experimental method

X-RAY DIFFRACTION (1.95 Å)