Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations.
X-ray crystal structures
anticancer agents
drug combinations
inhibition kinetics
synergistic combination
thymidylate synthase
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
24 Apr 2021
24 Apr 2021
Historique:
received:
19
03
2021
revised:
20
04
2021
accepted:
20
04
2021
entrez:
30
4
2021
pubmed:
1
5
2021
medline:
1
5
2021
Statut:
epublish
Résumé
Combining drugs represent an approach to efficiently prevent and overcome drug resistance and to reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors of the same enzyme target are considered. To show that crystallographic and inhibition kinetic information can provide indicators of cancer cell growth inhibition by combinations of two anti-human thymidylate synthase (hTS) drugs, we obtained the X-ray crystal structure of the hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex. Its analysis showed a ternary complex with both molecules strongly bound inside the enzyme catalytic cavity. The synergistic inhibition of hTS and its mechanistic rationale were consistent with the structural analysis. When administered in combination to A2780 and A2780/CP ovarian cancer cells, the two drugs inhibited ovarian cancer cell growth additively/synergistically. Together, these results support the idea that X-ray crystallography can provide structural indicators for designing combinations of hTS (or any other target)-directed drugs to accelerate preclinical research for therapeutic application.
Identifiants
pubmed: 33923290
pii: cancers13092061
doi: 10.3390/cancers13092061
pmc: PMC8123127
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 16977
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