From PARP1 to TNKS2 inhibition: A structure-based approach
Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
Compounds of Formula I are useful inhibitors of tankyrase. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
-
Paragraph 0185
(2014/03/25)
Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors
Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
Hua, Zihao,Bregman, Howard,Buchanan, John L.,Chakka, Nagasree,Guzman-Perez, Angel,Gunaydin, Hakan,Huang, Xin,Gu, Yan,Berry, Virginia,Liu, Jingzhou,Teffera, Yohannes,Huang, Liyue,Egge, Bryan,Emkey, Renee,Mullady, Erin L.,Schneider, Steve,Andrews, Paul S.,Acquaviva, Lisa,Dovey, Jennifer,Mishra, Ankita,Newcomb, John,Saffran, Douglas,Serafino, Randy,Strathdee, Craig A.,Turci, Susan M.,Stanton, Mary,Wilson, Cindy,Dimauro, Erin F.
p. 10003 - 10015
(2014/01/17)
More Articles about upstream products of 313233-21-5