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Target nature : inhibition of CDA-deficient tumor cells
CAS n° : 67243-03-2
Mecanism of action : /
Physico-chemical properties : M.W : 216.23 g/mol
Probe availability : Institut Curie/CNRS Chemical library
Princeps reference : Cytidine deaminase (CDA) expression is downregulated in about 60% of cancer cells and tissues. We identified a naphthol derivative, X55, targeting CDA-deficient tumor cells preferentially, without affecting the growth of non-tumoral cells regardless of CDA expression status. Metabolomic profiling revealed that CDA-deficient HeLa cells differed markedly from control HeLa cells. X55 treatment had a moderate effect on control cells, but greatly disturbed the metabolome of CDA-deficient HeLa cells, worsening the deregulation of many metabolites. In particular, the levels of the three oncometabolites, fumarate, succinate and 2-hydroxyglutarate, were significantly lower in CDA-depleted cells, and this decrease in levels was exacerbated by X55 treatment, revealing an unexpected link between CDA deficiency, mitochondrial function and X55 response. Finally, we identified strong downregulation of MAPT (encoding Tau, a microtubule associated protein) expression as a reliable predictive marker for tumor cell X55 sensitivity
More bibliography : 1) Mameri, H., Buhagiar-Labarchede, G., Fontaine, G., Corcelle, C., Barette, C., Onclercq-Delic, R., Beauvineau, C., Mahuteau-Betzer*, F., and Amor-Gueret*, M. (Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease in oncometabolite levels. Cell Mol Life Sci 79, 465. DOI: 10.1007/s00018-022-04487, 2022 2 )WO2022 061772 Naphtalene derivatives useful in the treatment of cancer Amor-Guéret, M.; Mameri, H.; Beauvineau, C.; Mahuteau-Betzer, F. déposé le 02/05/2022
Other available information on the probe : storage at rt, good chemical stability Solubility (in PBS) = 35 ± 3 µM Log D à pH 7.4 =3,48 ± 0,05 (exp) metabolic stability : T1/2 vie : 2,7 ± 0,1 min plasmatic stability : stable compound Liaison aux protéines plasmatiques : % lié = 99 ± 1% PAMPA : Log Pe = -5,69 ± 0,01
Other information on the target : /
Selectivity profile : X55 inhibited the growth of 40% of CDA-deficient tumor cell lines (8 of 20) and 22% of CDA-proficient tumor cell lines (2 of 9), without affecting the growth of non-tumor cell lines, regardless of CDA expression status
In vivo data : /
In vitro data : After 72h incubation of 1µM of X55 : 0% survival of HeLa-shCDA 100 % survival of HeLa 0 % survival of BT20 (CDA-) 10 % survival of MDA-MB-468 (CDA-) 10 % survival of MCF-7 (CDA-) 100 % survival of MDA-MB-436 (CDA+) 90 % survival of HCC-1937 (CDA+) 100 % survival of MDA-MB-231 (CDA+)
Toxicity : In cellulo : no toxicity on non-tumor cell lines
Chaine SMILES : COc1ccc(C=O)c2c(O)cccc12
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