2. Academic Validation
  3. New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action

New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action

  • Eur J Med Chem. 2023 Jan 15;246:115003. doi: 10.1016/j.ejmech.2022.115003.
Pilar M Luque-Navarro 1,  M Paz Carrasco-Jiménez 2,  Laura Goracci 3,  Jose M Paredes 4,  Laura Espinar-Barranco 4,  Javier Valverde-Pozo 4,  Archimede Torretta 5,  Emilio Parisini 6,  Elena Mariotto 7,  Chiara Marchioro 7,  Alejandro Laso 8,  Carmen Marco 8,  Giampietro Viola 9,  Daniela Lanari 10,  Luisa Carlota López Cara 11
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain; Department of Pharmaceutical Sciences, University of Perugia, Perugia, 06123 Italy.
  • 2 Department of Biochemistry and Molecular Biology I, University of Granada, Campus of Fuentenueva s/n, Granada, 18071, Spain. Electronic address: [email protected].
  • 3 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, 06123, Italy.
  • 4 Department of Physical-Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain.
  • 5 Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, Milano, 20133, Italy.
  • 6 Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, Milano, 20133, Italy; Department of Biotechnology, Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV, 1006, Latvia; Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, Bologna, 40126, Italy.
  • 7 Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Padova, 35128, Italy.
  • 8 Department of Biochemistry and Molecular Biology I, University of Granada, Campus of Fuentenueva s/n, Granada, 18071, Spain.
  • 9 Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Padova, 35128, Italy; Istituto di Ricerca Pediatrica (IRP) Fondazione Città della Speranza, Corso Stati Uniti 4, Padova, 35128, Italy. Electronic address: [email protected].
  • 10 Department of Pharmaceutical Sciences, University of Perugia, Perugia, 06123 Italy. Electronic address: [email protected].
  • 11 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain. Electronic address: [email protected].
PMID: 36493617 DOI: 10.1016/j.ejmech.2022.115003
Abstract

Since the identification of human choline kinase as a protein target against Cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg2+ cofactor, or its destabilization. The most active compounds of the two series are capable of inducing Apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response.

Keywords

Antitumoral drug; Bioisosterism; Choline kinase inhibition; Environmental synthesis.

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