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
  • 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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