Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat

Barrett, Ryan R.G.; Nash, Christopher; Diennet, Marine; Cotnoir-White, David; Doyle, Chris; Mader, Sylvie; Thomson, Axel A.; Gleason, James L.

doi:10.1016/j.bmcl.2021.128441

Cited by 3 publications

(2 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This work explores the in vitro potential of new hybrid compounds that simultaneously target two sites of the AR, the N‐terminal domain (NTD) and the ligand binding domain (LBD) (Figure 1). A dual target strategy by covalently linking enzalutamide to another drug has been recently successfully implemented for the development of dual inhibitors between enzalutamide and etinostat, a histone deacetylase inhibitor [16] . Similarly, there are extensive precedents for the success of heterobifunctional molecules, such as PROTACs, [17] bifunctional therapeutics [18] and multitarget compounds [19] .…”

Section: Introductionmentioning

confidence: 99%

“…A dual target strategy by covalently linking enzalutamide to another drug has been recently successfully implemented for the development of dual inhibitors between enzalutamide and etinostat, a histone deacetylase inhibitor. [16] Similarly, there are extensive precedents for the success of heterobifunctional molecules, such as PROTACs, [17] bifunctional therapeutics [18] and multitarget compounds. [19] Moreover, significant efforts in moving away from conventional active site targeting have been attempted up to date.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI‐001 in in vitro Models of Prostate Cancer Drug Resistance

et al. 2022

View full text Add to dashboard Cite

Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display an 18 to 53 fold improvement in the cell killing potency towards C4-2b prostate cancer (PCa) cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through androgen receptor (AR) mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties -EPI-001 and enzalutamide -into the same molecule.

show abstract