4l5b Citations

Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.

Abstract

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = ∼1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.

Articles citing this publication (5)

  1. Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication. Nathanson DA, Armijo AL, Tom M, Li Z, Dimitrova E, Austin WR, Nomme J, Campbell DO, Ta L, Le TM, Lee JT, Darvish R, Gordin A, Wei L, Liao HI, Wilks M, Martin C, Sadeghi S, Murphy JM, Boulos N, Phelps ME, Faull KF, Herschman HR, Jung ME, Czernin J, Lavie A, Radu CG. J. Exp. Med. 211 473-486 (2014)
  2. Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes. Moroz MA, Zhang H, Lee J, Moroz E, Zurita J, Shenker L, Serganova I, Blasberg R, Ponomarev V. J. Nucl. Med. 56 1055-1060 (2015)
  3. Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability. Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A. J. Med. Chem. 57 9480-9494 (2014)
  4. [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Kim W, Le TM, Wei L, Poddar S, Bazzy J, Wang X, Uong NT, Abt ER, Capri JR, Austin WR, Van Valkenburgh JS, Steele D, Gipson RM, Slavik R, Cabebe AE, Taechariyakul T, Yaghoubi SS, Lee JT, Sadeghi S, Lavie A, Faull KF, Witte ON, Donahue TR, Phelps ME, Herschman HR, Herrmann K, Czernin J, Radu CG. Proc. Natl. Acad. Sci. U.S.A. 113 4027-4032 (2016)
  5. Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists. Ma L, Wang T, Shi M, Fu P, Pei H, Ye H. Chem Biol Drug Des 88 26-37 (2016)