2. Academic Validation
  3. Discovery of first-in-class imidazothiazole-based potent and selective ErbB4 (HER4) kinase inhibitors

Discovery of first-in-class imidazothiazole-based potent and selective ErbB4 (HER4) kinase inhibitors

  • Eur J Med Chem. 2021 Nov 15:224:113674. doi: 10.1016/j.ejmech.2021.113674.
Seyed-Omar Zaraei 1,  Rawan M Sbenati 2,  Nour N Alach 2,  Hanan S Anbar 3,  Randa El-Gamal 4,  Hamadeh Tarazi 5,  Mahmoud K Shehata 2,  Mohammed S Abdel-Maksoud 6,  Chang-Hyun Oh 1,  Mohammed I El-Gamal 7
Affiliations

Affiliations

  • 1 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
  • 2 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 3 Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates. Electronic address: dr.hanan@dpc.edu.
  • 4 Department of Medical Biochemistry, Faculty of Medicine, University of Mansoura, Mansoura, 35516, Egypt.
  • 5 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 6 Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618)), Dokki, Giza, 12622, Egypt.
  • 7 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt. Electronic address: malgamal@sharjah.ac.ae.
PMID: 34237622 DOI: 10.1016/j.ejmech.2021.113674
Abstract

This article reports on novel imidazothiazole derivatives as first-in-class potent and selective ErbB4 (HER4) inhibitors. There are no Other reported selective inhibitors of this kinase in the literature, that's why they are considered as first-in-class. In addition, none of the reported non-selective ErbB4 inhibitors possesses imidazothiazole nucleus in its structure. Therefore, there is novelty in this work in both kinase selectivity and chemical structure. Compounds Ik and IIa are the most potent ErbB4 kinase inhibitor (IC50 = 15.24 and 17.70 nM, respectively). Compound Ik showed promising antiproliferative activity. It is selective towards Cancer cell lines than normal cells. Its ability to penetrate T-47D cell membrane and inhibit ErbB4 kinase inside the cells has been confirmed. Moreover, both compound Ik and IIa have additional merits such as weak potency against hERG ion channels and against CYP 3A4 and 2D6. Molecular docking and dynamic simulation studies were carried out to explain binding interactions.

Keywords

Antiproliferative; ErbB4; HER4; Imidazo[2,1-b]thiazole; Kinase inhibitor.

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