Choline kinase (ChoK) has been well documented as a major enzyme involved in the anomalous cellular lipid metabolic profile of chronic inflammatory disorders. However, new research has now been unveiled that helps us to better understand how changes in lipid metabolism influence the transformational phenotype, drug resistance, and antiapoptotic characteristics of invasive cells, leading to rheumatoid arthritis (RA) disease progression. It is still unknown how ChoK modulates the lipid metabolic aberrations that may promote altered cell phenotype and functionality in RA. Herein, we review the current understanding of ChoK's role in altered metabolism in diverse cell types involved in RA progression, and for the first time, we take a step forward to complete the puzzle and summarise striking facts that link choline metabolism to its transformed phenotype, in order to postulate ChoK as a robust therapeutic target in RA. This review forms a foundation on which ChoK can be tackled as a potential biomarker, opening doors for RA diagnosis and prognosis. It frameworks several ChoK inhibitors that rewire the lipid metabolic profile in the inflammatory disease landscape and envisages its being translated to clinics.

01 Nov 2021·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Identification of unprecedented ATP-competitive choline kinase inhibitors

Q4 · MEDICINE

Article

Author: Corti, Emiliana ; Borghi, Daniela ; Lomolino, Antonio ; Riccardi-Sirtori, Federico ; Casale, Elena ; Salsi, Enea ; Nesi, Marcella ; Isacchi, Antonella ; Perrera, Claudia ; Avanzi, Nilla R ; Re Depaolini, Stefania ; Fasolini, Marina ; Donati, Daniele ; Giorgini, Maria L ; Galvani, Arturo ; Felder, Eduard R ; Quartieri, Francesca ; Gnocchi, Paola ; Orrenius, Christian ; Cucchi, Ulisse ; Menichincheri, Maria

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.

01 Mar 2021·Medicinal Research ReviewsQ1 · MEDICINE

Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition

Q1 · MEDICINE

Review

Author: Hurtado‐Guerrero, Ramón ; Serrán‐Aguilera, Lucía ; Conejo‐García, Ana ; Rubio‐Ruiz, Belén

AbstractUpregulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline‐binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multifunctional potent drugs for the treatment of various human diseases.

100 Deals associated with NMS-P830

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Indication	Highest Phase	Country/Location	Organization	Date
Myeloproliferative Disorders	Preclinical	IT	Nerviano Medical Sciences S.r.l	-
Solid tumor	Preclinical	IT	Fondazione Irccs Istituto Nazionale Dei Tumori	-
Solid tumor	Preclinical	IT	Nerviano Medical Sciences S.r.l	-

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