2. Academic Validation
  3. Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase

Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase

  • Bioorg Med Chem. 2021 Feb 1:31:115962. doi: 10.1016/j.bmc.2020.115962.
Dabbugoddu Brahmaiah 1,  Anagani Kanaka Durga Bhavani 2,  Pasula Aparna 3,  Nangunoori Sampath Kumar 4,  Hélène Solhi 5,  Rémy Le Guevel 5,  Blandine Baratte 6,  Sandrine Ruchaud 7,  Stéphane Bach 6,  Surender Singh Jadav 8,  Chada Raji Reddy 8,  Thierry Roisnel 9,  Paul Mosset 9,  Nicolas Levoin 10,  René Grée 11
Affiliations

Affiliations

  • 1 Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad 500039, Telangana, India; Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500 085, Telangana, India.
  • 2 Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India.
  • 3 Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500 085, Telangana, India.
  • 4 Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad 500039, Telangana, India.
  • 5 Univ Rennes, Plateform ImPACcell, BIOSIT, F-35000 Rennes, France.
  • 6 Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, CS 90074, 29688 Roscoff Cedex, France; Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, CS 90074, 29688 Roscoff Cedex, France.
  • 7 Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, CS 90074, 29688 Roscoff Cedex, France.
  • 8 CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, TS, India.
  • 9 Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France.
  • 10 Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint Grégoire, France.
  • 11 Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France. Electronic address: rene.gree@univ-rennes1.fr.
PMID: 33422908 DOI: 10.1016/j.bmc.2020.115962
Abstract

We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven Cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 μM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.

Keywords

Cancer; Kinases; Molecular modelling; Quinazolines; Triazoles.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-131978
    98.27%, CLK Inhibitor
    CDK