Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase.
Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 μM and activity against ovarian cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits anticancer activity against ovarian cancer cells.
Dipartimento di Chimica,  Università degli Studi di Perugia , Via Elce di Sotto 10, 06123, Perugia, Italy.
Emanuele
E
Carosati
Anna
A
Tochowicz
Gaetano
G
Marverti
Giambattista
G
Guaitoli
Paolo
P
Benedetti
Stefania
S
Ferrari
Robert M
RM
Stroud
Janet
J
Finer-Moore
Rosaria
R
Luciani
Davide
D
Farina
Gabriele
G
Cruciani
M Paola
MP
Costi
D000083:Acetanilides / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
C577962:2-(4-hydroxy-2-((2-hydroxybenzylidene)hydrazono)-2,5-dihydrothiazol-5-yl)-N-(3-trifluoromethylphenyl)acetamide; D000083:Acetanilides; D000970:Antineoplastic Agents; D013844:Thiazoles; D013940:Thymidylate Synthase; D002945:Cisplatin