2. Academic Validation
  3. Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker

Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker

  • Eur J Med Chem. 2022 Aug 5;238:114411. doi: 10.1016/j.ejmech.2022.114411.
Dalia S El-Gamil 1,  Ahmed K ElHady 2,  Po-Jen Chen 3,  Tsong-Long Hwang 4,  Ashraf H Abadi 5,  Mohammad Abdel-Halim 6,  Matthias Engel 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt; Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo, 12451, Egypt. Electronic address: daliashgamil@gmail.com.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt; School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, 11865, Egypt. Electronic address: a.kamal@gaf.edu.eg.
  • 3 Department of Medical Research, E-Da Hospital, Kaohsiung, 824005, Taiwan. Electronic address: ed113510@edah.org.tw.
  • 4 Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, 243, Taiwan. Electronic address: htl@mail.cgu.edu.tw.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: mohammad.abdel-halim@guc.edu.eg.
  • 7 Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123, Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de.
PMID: 35635953 DOI: 10.1016/j.ejmech.2022.114411
Abstract

As prime regulators of pre-mRNA alternative splicing, different CLK isoforms were found to be overexpressed in various tumour types and have received much attention recently as potential targets for Cancer therapy. Several studies have reported potent small-molecule Clk1/4 inhibitors with promising cellular anti-cancer activities; however, their clinical use was generally hampered by their compromised selectivity against off-targets, mainly Clk2 and Dyrk1A. In this study, we present a novel series of N-aroylated 5-methoxybenzothiophene-2-carboxamides (imides) as potent and selective Clk1/4 inhibitors. Potency of this series was found to be mainly dependent on the presence of an intramolecular H-bond between an ortho-methoxy group and the imide NH, that stabilizes a nearly coplanar conformation of high affinity to the ATP binding pocket(s) of Clk1/4. The two most potent hits in this series, compounds 20 (4-fluoro-2-methoxy) and 31 (5-chloro-2-methoxy) had cell free Clk1 IC50s of 4 and 9.7 nM, respectively, besides an unprecedented selectivity over Clk2 with 62- and 50-times higher affinities towards Clk1, respectively. 20 and 31 also exhibited remarkable selectivity over most common off-targets including Dyrk1A. Moreover, compounds 26 (2-ethoxy) and 31 showed growth inhibitory activities in T24 Cancer cells with GI50s of <0.1 and 1.1 μM, respectively.

Keywords

Anticancer agents; Benzothiophenes; Clk1; Imides; Intramolecular hydrogen bond; Kinase inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146335
    Clk1/4 Inhibitor
    CDK