1. Academic Validation
  2. Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

  • J Nat Prod. 2022 Jun 24;85(6):1503-1513. doi: 10.1021/acs.jnatprod.1c01222.
Muhammad Furqan 1 Alishba Fayyaz 1 Farhat Firdous 1 2 Hadeeqa Raza 1 Aishah Bilal 1 Rahman Shah Zaib Saleem 2 Syed Shahzad-Ul-Hussan 1 Daijie Wang 3 Fadia S Youssef 4 Nawal M Al Musayeib 5 Mohamed L Ashour 4 Hidayat Hussain 6 Amir Faisal 1
Affiliations

Affiliations

  • 1 Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
  • 2 Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
  • 3 School of Pharmaceutical Sciences and Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
  • 4 Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Abbasia, Cairo 11566, Egypt.
  • 5 Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 6 Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Abstract

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of Quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several Quinones as inhibitors. IC50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin (11), potently inhibited the proliferation of various Cancer cell lines with IC50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 μM, respectively. Treatment of Cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified Quinones as Aurora Kinase inhibitors that can serve as a lead for future drug discovery endeavors.

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