Discovery of 3-phenyl- and 3-N-piperidinyl-isothiazolo[4,3-b]pyridines as highly potent inhibitors of cyclin G-associated kinase

Eur J Med Chem. 2021 Mar 5:213:113158. doi: 10.1016/j.ejmech.2021.113158.

Belén Martinez-Gualda ¹, Sirle Saul ², Mathy Froeyen ¹, Dominique Schols ³, Piet Herdewijn ¹, Shirit Einav ², Steven De Jonghe ⁴

Affiliations

1 KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, 3000, Leuven, Belgium.
2 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
3 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000, Leuven, Belgium.
4 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000, Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.

PMID: 33497888 DOI: 10.1016/j.ejmech.2021.113158

Abstract

Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety generated potent GAK inhibitors with IC₅₀ values in a low nanomolar range. This potent GAK binding affinity was rationalized by molecular modelling demonstrating that the carboxamide moiety engages in an extra hydrogen bond with GAK. Moreover, this new series of compounds was also endowed with Antiviral activity against Dengue virus, highlighting the potential utility of GAK as a target for the development of Antiviral drugs.

Keywords

Antiviral agents; Cyclin G-associated kinase; Dengue virus; Isothiazolo[4,3-b]pyridine; Kinase inhibitor.

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