Open AccessNovel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β
Author(s) -
J.A. Ortega,
José M. Arencibia,
Elirosa Minniti,
Jo Ann W. Byl,
Sebastian Franco-Ulloa,
Marco Borgogno,
Vito Genna,
Maria Summa,
Sine Mandrup Bertozzi,
Rosalia Bertorelli,
Andrea Armirotti,
Anna Minarini,
Claudia Sissi,
Neil Osheroff,
Marco De Vivo
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00774
Subject(s) - chemistry , topoisomerase , etoposide , in vivo , topoisomerase inhibitor , pharmacology , ic50 , drug , dna , in vitro , biochemistry , biology , chemotherapy , microbiology and biotechnology , genetics
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) IC 50 = 2 μM for inhibition of DNA relaxation, as compared to an IC 50 = 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.