Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK

Sandeep Rana, Smit Kour, Yogesh A. Sonawane, Caroline M. Robb, Jacob I. Contreras, Smitha Kizhake, Muhammad Zahid, Adam R. Karpf, Amarnath Natarajan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)773-784
Number of pages12
JournalChemical Biology and Drug Design
Volume96
Issue number2
DOIs
StatePublished - Aug 1 2020

Keywords

  • CDK
  • NFkappaB
  • prodrugs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK'. Together they form a unique fingerprint.

Cite this