Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.
4-Butyrolactone
/ analogs & derivatives
Amines
/ chemistry
Antineoplastic Agents
/ chemical synthesis
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cyclin-Dependent Kinases
/ metabolism
Drug Screening Assays, Antitumor
Female
Humans
Molecular Targeted Therapy
NF-kappa B
/ metabolism
Ovarian Neoplasms
/ drug therapy
Piperazines
/ chemical synthesis
Piperidines
/ chemical synthesis
Prodrugs
/ chemistry
Protein Kinase Inhibitors
/ chemical synthesis
Pyrazoles
/ chemical synthesis
Pyridines
/ chemical synthesis
Sesquiterpenes
/ chemical synthesis
Signal Transduction
Structure-Activity Relationship
CDK
NFkappaB
prodrugs
Journal
Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
24
01
2020
revised:
04
03
2020
accepted:
14
03
2020
pubmed:
3
4
2020
medline:
23
6
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.
Identifiants
pubmed: 32237047
doi: 10.1111/cbdd.13684
pmc: PMC8022330
mid: NIHMS1681750
doi:
Substances chimiques
4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide
0
Amines
0
Antineoplastic Agents
0
NF-kappa B
0
Piperazines
0
Piperidines
0
Prodrugs
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyridines
0
Sesquiterpenes
0
parthenolide
2RDB26I5ZB
alpha-methylene gamma-butyrolactone
362Y256BOL
Cyclin-Dependent Kinases
EC 2.7.11.22
palbociclib
G9ZF61LE7G
4-Butyrolactone
OL659KIY4X
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
773-784Subventions
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197999
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA182820
Pays : United States
Informations de copyright
© 2020 John Wiley & Sons A/S.
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