Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells.
Antineoplastic Agents
/ chemical synthesis
BRCA2 Protein
/ genetics
Cell Line, Tumor
Drug Synergism
Homologous Recombination
/ drug effects
Humans
Molecular Mimicry
Mutation
Pancreatic Neoplasms
/ drug therapy
Phthalazines
/ therapeutic use
Piperazines
/ therapeutic use
Protein Binding
/ drug effects
Rad51 Recombinase
/ metabolism
Triazoles
/ chemical synthesis
Anticancer drugs
Homologous recombination
PARP inhibitors
Protein-protein small molecule inhibitors
Synthetic lethality
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Mar 2019
01 Mar 2019
Historique:
received:
19
10
2018
revised:
03
01
2019
accepted:
04
01
2019
pubmed:
21
1
2019
medline:
22
3
2019
entrez:
21
1
2019
Statut:
ppublish
Résumé
Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
Identifiants
pubmed: 30660828
pii: S0223-5234(19)30008-X
doi: 10.1016/j.ejmech.2019.01.008
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA2 Protein
0
BRCA2 protein, human
0
Phthalazines
0
Piperazines
0
Triazoles
0
Rad51 Recombinase
EC 2.7.7.-
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
80-92Informations de copyright
Copyright © 2019. Published by Elsevier Masson SAS.