Open AccessFrom PARP1 to TNKS2 Inhibition: A Structure-Based Approach
Author(s) -
Stefano Tomassi,
Julian Pfahler,
Nicola Mautone,
Annarita Rovere,
Chiara Esposito,
Daniela Passeri,
Roberto Pellicciari,
Ettore Novellino,
M. Pannek,
Clemens Steegborn,
Alessandro Paiardini,
Antonello Mai,
Dante Rotili
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00654
Subject(s) - wnt signaling pathway , parp1 , virtual screening , cancer research , drug discovery , chemistry , computational biology , microbiology and biotechnology , biology , biochemistry , signal transduction , enzyme , poly adp ribose polymerase , polymerase
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.