PMID: 11297449Apr 12, 2001Paper

Molecular models of N-benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-delta

Journal of Medicinal Chemistry
J B RoatenA L Parrill

Abstract

N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline with experimental antitumor activity superior to that of doxorubicin (DOX). AD 198, unlike DOX, only weakly binds DNA, is a poor inhibitor of topoisomerase II, and circumvents anthracycline-resistance mechanisms, suggesting a unique mechanism of action for this novel analogue. The phorbol ester receptors, protein kinase C (PKC) and beta2-chimaerin, were recently identified as selective targets for AD 198 in vitro. In vitro, AD 198 competes with [3H]PDBu for binding to a peptide containing the isolated C1b domain of PKC-delta (deltaC1b domain). In the present study molecular modeling is used to investigate the interaction of AD 198 with the deltaC1b domain. Three models are identified wherein AD 198 binds into the groove formed between amino acid residues 6-13 and 21-27 of the deltaC1b domain in a manner similar to that reported for phorbol-13-acetate and other ligands of the C1 domain. Two of the identified models are consistent with previous experimental data demonstrating the importance of the 14-valerate side chain of AD 198 in binding to the C1 domain as well as current data demonstrating that translocation of PKC-alpha to the membrane requires the 14-...Continue Reading

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Citations

Jun 1, 2010·Breast Cancer Research and Treatment·María Ines Díaz BessoneAlejandro J Urtreger
Jun 18, 2010·Carcinogenesis·Stine M AndersenKarin Stenderup
Jul 30, 2010·The Journal of Pharmacology and Experimental Therapeutics·Chun CaiPolly A Hofmann
Nov 7, 2014·Chemical Reviews·Joydip Das, Ghazi M Rahman
Apr 18, 2015·Surgical Neurology International·Anthony Samsel, Stephanie Seneff
Mar 27, 2004·Molecular Pharmacology·Jennifer D BilyeuMarcello Arsura
Aug 19, 2007·The Journal of Pharmacology and Experimental Therapeutics·Polly A HofmannLeonard Lothstein
May 21, 2020·Oncology Research·Leonard LothsteinTiffany Seagroves
Jan 5, 2002·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·L LothsteinT W Sweatman

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