View source for 7ocv


==Human TNKS1 in complex with 3-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-6-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one==
<StructureSection load='7ocv' size='340' side='right'caption='[[7ocv]], [[Resolution|resolution]] 1.43&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OCV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OCV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.432&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=V8B:6-methyl-3-[4-(2-oxidanylpropan-2-yl)phenyl]-4~{H}-pyrrolo[1,2-a]pyrazin-1-one'>V8B</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ocv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ocv OCA], [https://pdbe.org/7ocv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ocv RCSB], [https://www.ebi.ac.uk/pdbsum/7ocv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ocv ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 M2912, 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 in vivo.

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models.,Buchstaller HP, 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 J Med Chem. 2021 Jul 22;64(14):10371-10392. doi: 10.1021/acs.jmedchem.1c00800., Epub 2021 Jul 13. PMID:34255518<ref>PMID:34255518</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ocv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Buchstaller H-P]]
[[Category: Lehmann M]]
[[Category: Musil D]]