1. Academic Validation
  2. Discovery of novel 5-methoxybenzothiophene hydrazides as metabolically stable Clk1 inhibitors with high potency and unprecedented Clk1 isoenzyme selectivity

Discovery of novel 5-methoxybenzothiophene hydrazides as metabolically stable Clk1 inhibitors with high potency and unprecedented Clk1 isoenzyme selectivity

  • Eur J Med Chem. 2023 Feb 5;247:115019. doi: 10.1016/j.ejmech.2022.115019.
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.
  • 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.
  • 3 Department of Medical Research, E-Da Hospital, Kaohsiung, 824005, Taiwan.
  • 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.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: [email protected].
  • 7 Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123, Saarbrücken, Germany. Electronic address: [email protected].
Abstract

Clk1 kinase is a key modulator of the pre-mRNA alternative splicing machinery which has been proposed as a promising target for treatment of various tumour types, Duchenne's muscular dystrophy and viral infections such as HIV-1 and influenza. Most reported Clk1 inhibitors showed significant co-inhibition of Clk2 and Clk4 in particular, which limits their usefulness for deciphering the individual roles of the Clk1 isoform in physiology and disease. Herein, we present a new 5-methoxybenzothiophene scaffold, enabling for the first time selective inhibition of Clk1 even among the isoenzymes. The 3,5-difluorophenyl and 3,5-dichlorophenyl derivatives 26a and 27a (Clk1 IC50 = 1.4 and 1.7 nM, respectively) showed unprecedented selectivity factors of 15 and 8 over Clk4, and selectivity factors of 535 and 84 over Clk2. Furthermore, 26a and 27a exhibited good growth inhibitory activity in T24 Cancer cells and long metabolic half-lives of almost 1 and 6.4 h, respectively. The overall favorable profile of our new Clk1 inhibitors suggests that they may be used in in vivo disease models or as probes to unravel the physiological or pathogenic roles of the Clk1 isoenzyme.

Keywords

Anticancer agents; Benzothiophenes; Chemical probes; Clk1; Hydrazides; Kinase inhibitors.

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