ArticleChemical biology & drug design2020
Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.
Article in Chemical biology & drug design, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Advancements in CDK-based Dual-target Inhibitors for Cancer Therapy.Current medicinal chemistry · 2026Review
- The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.Hemato · 2024Article
- Domino Reactions Enable Zn-Mediated Direct Synthesis of Spiro-Fused 2-Oxindole-α-Methylene-γ-Butyrolactones/Lactams from Isatin Derivatives and 2-(Bromomethyl)acrylates.Molecules (Basel, Switzerland) · 2024Article
- Design, synthesis, and evaluation of a mitoxantrone probe (MXP) for biological studies.Bioorganic & medicinal chemistry letters · 2023Article
- Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario.Pharmaceutics · 2023Review
- Dimers of isatin derived α-methylene-γ-butyrolactone as potent anti-cancer agents.Bioorganic & medicinal chemistry letters · 2022Article
- Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.The Journal of biological chemistry · 2022Article
- Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA.RSC chemical biology · 2022Article
- Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase.Cancers · 2021Review
- Structure activity relationship (SAR) study identifies a quinoxaline urea analog that modulates IKKβ phosphorylation for pancreatic cancer therapy.European journal of medicinal chemistry · 2021Article
- Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax.Bioorganic & medicinal chemistry letters · 2021Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.