7OCV

Human TNKS1 in complex with 3-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-6-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one

7OCV の概要

• エントリーDOI: 10.2210/pdb7ocv/pdb
• 分子名称: 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)
• 機能のキーワード: tankyrase, parp, inhibitor, transferase-transferase inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24695.36

構造登録者

Musil, D.,Lehmann, M.,Buchstaller, H.-P. (登録日: 2021-04-28, 公開日: 2021-07-28, 最終更新日: 2024-11-20)

主引用文献

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

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: 34255518
DOI: 10.1021/acs.jmedchem.1c00800

実験手法

X-RAY DIFFRACTION (1.432 Å)