2. Academic Validation
  3. Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β

Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β

  • J Med Chem. 2020 Nov 12;63(21):12873-12886. doi: 10.1021/acs.jmedchem.0c00774.
Jose Antonio Ortega 1,  Jose M Arencibia 1,  Elirosa Minniti 1 2,  Jo Ann W Byl 3,  Sebastian Franco-Ulloa 1,  Marco Borgogno 1,  Vito Genna 1,  Maria Summa 4,  Sine Mandrup Bertozzi 4,  Rosalia Bertorelli 4,  Andrea Armirotti 4,  Anna Minarini 2,  Claudia Sissi 5,  Neil Osheroff 3 6 7,  Marco De Vivo 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • 3 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.
  • 4 Analytical Chemistry & Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 5 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
  • 6 Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307, United States.
  • 7 VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States.
PMID: 33079544 DOI: 10.1021/acs.jmedchem.0c00774
Abstract

We disclose a novel class of 6-amino-tetrahydroquinazoline derivatives that inhibit human Topoisomerase II (topoII), a validated target of Anticancer drugs. In contrast to topoII-targeted drugs currently in clinical use, these compounds do not act as topoII poisons that enhance enzyme-mediated DNA cleavage, a mechanism that is linked to the development of secondary leukemias. Instead, these tetrahydroquinazolines block the topoII function with no evidence of DNA intercalation. We identified a potent lead compound [compound 14 (ARN-21934) IC50 = 2 μM for inhibition of DNA relaxation, as compared to an IC50 = 120 μM for the Anticancer drug etoposide] with excellent metabolic stability and solubility. This new compound also shows ~100-fold selectivity for topoIIα over topoβ, a broad antiproliferative activity toward cultured human Cancer cells, a favorable in vivo pharmacokinetic profile, and the ability to penetrate the blood-brain barrier. Thus, ARN-21934 is a highly promising lead for the development of novel and potentially safer topoII-targeted Anticancer drugs.

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