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Identification of unprecedented ATP-competitive choline kinase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Nov 01; Vol. 51, pp. 128310. Date of Electronic Publication: 2021 Aug 18. - Publication Year :
- 2021
-
Abstract
- In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adenosine Triphosphate metabolism
Choline Kinase metabolism
Cyclohexanes chemical synthesis
Cyclohexanes chemistry
Dose-Response Relationship, Drug
Humans
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Structure-Activity Relationship
Adenosine Triphosphate antagonists & inhibitors
Choline Kinase antagonists & inhibitors
Cyclohexanes pharmacology
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 51
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34416377
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.128310