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

Dabbugoddu Brahmaiah; Anagani Kanaka Durga Bhavani; Pasula Aparna; Nangunoori Sampath Kumar; Hélène Solhi; Rémy Le Guevel; Blandine Baratte; Sandrine Ruchaud; Stéphane Bach; Surender Singh Jadav; Chada Raji Reddy; Thierry Roisnel; Paul Mosset; Nicolas Levoin; René Grée

doi:10.1016/j.bmc.2020.115962

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. Epub 2020 Dec 31.

Authors

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Dyrk Kinases
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases