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From PARP1 to TNKS2 Inhibition : A Structure-Based Approach

Title data

Tomassi, Stefano ; Pfahler, Julian ; Mautone, Nicola ; Rovere, Anarita ; Esposito, Chiara ; Passeri, Daniela ; Pellicciari, Roberto ; Novellino, Ettore ; Pannek, Martin ; Steegborn, Clemens ; Paiardini, Alessandro ; Mai, Antonello ; Rotili, Dante:
From PARP1 to TNKS2 Inhibition : A Structure-Based Approach.
In: ACS Medicinal Chemistry Letters. Vol. 11 (February 2020) Issue 5 . - pp. 862-868.
ISSN 1948-5875
DOI: https://doi.org/10.1021/acsmedchemlett.9b00654

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 07 Sep 2020 08:00
Last Modified: 07 Sep 2020 08:00
URI: https://eref.uni-bayreuth.de/id/eprint/56814