7OCV
Human TNKS1 in complex with 3-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-6-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one
Summary for 7OCV
| Entry DOI | 10.2210/pdb7ocv/pdb |
| Descriptor | Poly [ADP-ribose] polymerase, ACETATE ION, 6-methyl-3-[4-(2-oxidanylpropan-2-yl)phenyl]-4~{H}-pyrrolo[1,2-a]pyrazin-1-one, ... (5 entities in total) |
| Functional Keywords | tankyrase, parp, inhibitor, transferase-transferase inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 24695.36 |
| Authors | Musil, D.,Lehmann, M.,Buchstaller, H.-P. (deposition date: 2021-04-28, release date: 2021-07-28, Last modification date: 2024-11-20) |
| Primary citation | Buchstaller, H.P.,Anlauf, U.,Dorsch, D.,Kogler, S.,Kuhn, D.,Lehmann, M.,Leuthner, B.,Lodholz, S.,Musil, D.,Radtki, D.,Rettig, C.,Ritzert, C.,Rohdich, F.,Schneider, R.,Wegener, A.,Weigt, S.,Wilkinson, K.,Esdar, C. Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models. J.Med.Chem., 64:10371-10392, 2021 Cited by PubMed Abstract: Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth. Herein, the identification of a screening hit series and its optimization through scaffold hopping and SAR exploration is described. The systematic assessment delivered , a compound with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compound in colorectal xenograft models . PubMed: 34255518DOI: 10.1021/acs.jmedchem.1c00800 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.432 Å) |
Structure validation
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