Identification of unprecedented ATP-competitive choline kinase inhibitors

DOI: 10.1016/j.bmcl.2021.128310

Authors: Francesca Quartieri (Nerviano Medical Sciences Srl) , Marcella Nesi (Nerviano Medical Sciences Srl) , Nilla R. Avanzi (Nerviano Medical Sciences Srl) , Daniela Borghi (Nerviano Medical Sciences Srl) , Elena Casale (Nerviano Medical Sciences Srl) , Emiliana Corti (Nerviano Medical Sciences Srl) , Ulisse Cucchi (Nerviano Medical Sciences Srl) , Daniele Donati (Nerviano Medical Sciences Srl) , Marina Fasolini (Nerviano Medical Sciences Srl) , Eduard R. Felder (Nerviano Medical Sciences Srl) , Arturo Galvani (Nerviano Medical Sciences Srl) , Maria L. Giorgini (Nerviano Medical Sciences Srl) , Antonio Lomolino (Nerviano Medical Sciences Srl) , Maria Menichincheri (Nerviano Medical Sciences Srl) , Christian Orrenius (Nerviano Medical Sciences Srl) , Claudia Perrera (Nerviano Medical Sciences Srl) , Stefania Re Depaolini (Nerviano Medical Sciences Srl) , Federico Riccardi-Sirtori (Nerviano Medical Sciences Srl) , Enea Salsi (Nerviano Medical Sciences Srl) , Antonella Isacchi (Nerviano Medical Sciences Srl) , Paola Gnocchi (Nerviano Medical Sciences Srl)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 51

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 26586

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.

Journal Keywords: Choline kinase; ATP; Metabolism; Inhibitors

Diamond Keywords: Breast Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 13/10/2021 09:05

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)