Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors

Anna Vulpetti; Elena Casale; Fulvia Roletto; Raffaella Amici; Manuela Villa; Paolo Pevarello

doi:10.1016/j.jmgm.2005.09.012

Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors

Anna Vulpetti, Elena Casale, Fulvia Roletto, Raffaella Amici, Manuela Villa, Paolo Pevarello

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

Abstract

N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC₅₀ = 808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3- thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC₅₀ = 20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.

Original language	English
Pages (from-to)	341-348
Number of pages	8
Journal	Journal of Molecular Graphics and Modelling
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.jmgm.2005.09.012
Publication status	Published - Mar 2006

Keywords

CDK2
Crystal structures
Cyclin-dependent kinase
Ligand docking
Ligand-protein interactions
Structure-based drug design

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Spectroscopy
Atomic and Molecular Physics, and Optics

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10.1016/j.jmgm.2005.09.012

Cite this

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abstract = "N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50 = 808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3- thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50 = 20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.",

keywords = "CDK2, Crystal structures, Cyclin-dependent kinase, Ligand docking, Ligand-protein interactions, Structure-based drug design",

author = "Anna Vulpetti and Elena Casale and Fulvia Roletto and Raffaella Amici and Manuela Villa and Paolo Pevarello",

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AU - Vulpetti, Anna

AU - Casale, Elena

AU - Roletto, Fulvia

AU - Amici, Raffaella

AU - Villa, Manuela

AU - Pevarello, Paolo

PY - 2006/3

Y1 - 2006/3

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AB - N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50 = 808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3- thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50 = 20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.

KW - CDK2

KW - Crystal structures

KW - Cyclin-dependent kinase

KW - Ligand docking

KW - Ligand-protein interactions

KW - Structure-based drug design

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Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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