From PARP1 to TNKS2 Inhibition: A Structure-Based Approach

Stefano Tomassi; Julian Pfahler; Nicola Mautone; Annarita Rovere; Chiara Esposito; Daniela Passeri; Roberto Pellicciari; Ettore Novellino; Martin Pannek; Clemens Steegborn; Alessandro Paiardini; Antonello Mai; Dante Rotili

doi:10.1021/acsmedchemlett.9b00654

From PARP1 to TNKS2 Inhibition: A Structure-Based Approach

ACS Med Chem Lett. 2020 Feb 3;11(5):862-868. doi: 10.1021/acsmedchemlett.9b00654. eCollection 2020 May 14.

Affiliations

¹ Department of Pharmacy, University of Naples, "Federico II", 80131 Naples, Italy.
² Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth, 95440 Bayreuth, Germany.
³ Department of Chemistry and Technology of Drugs, ″Sapienza" University of Rome, 00185 Rome, Italy.
⁴ Department of Biochemical Sciences "A. Rossi Fanelli″, ″Sapienza" University of Rome, 00185 Rome, Italy.
⁵ TES Pharma S.r.l., 06073 Corciano, Perugia, Italy.

Abstract

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.