2. Academic Validation
  3. From PARP1 to TNKS2 Inhibition: A Structure-Based Approach

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.
Stefano Tomassi 1,  Julian Pfahler 2,  Nicola Mautone 3,  Annarita Rovere 3,  Chiara Esposito 4,  Daniela Passeri 5,  Roberto Pellicciari 5,  Ettore Novellino 1,  Martin Pannek 2,  Clemens Steegborn 2,  Alessandro Paiardini 4,  Antonello Mai 3,  Dante Rotili 3
Affiliations

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.
PMID: 32435397 DOI: 10.1021/acsmedchemlett.9b00654
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.

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