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

Abstract

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.

Current and emerging approaches to noncompetitive AR inhibition

“…115,127 Very recently, Asim and Spring reported the combination of two covalently linked AR inhibitors, EPI-001 and enzalutamide (Figure 18). 130 The strategy was aimed at appending enzalutamide via the amide portion to the 1,2- Despite the advantages of targeting multiple domains of the AR, compound 9b will potentially suffer from poor pharmacokinetic properties due to high MW, HBA, TPSA, and rotatable bond count inferring poor solubility and membrane permeability. Asim and Spring stated that the compounds could have limited membrane permeability as they were less potent than enzalutamide in the luciferase assay, although cLogP and HBD for the compound are within Lipinski's rules.…”

“…Very recently, Asim and Spring reported the combination of two covalently linked AR inhibitors, EPI‐001 and enzalutamide (Figure 18). 130 The strategy was aimed at appending enzalutamide via the amide portion to the 1,2‐diol of EPI‐001 through an epoxide opening maintaining the active chlorohydrin pharmacophore. Utilizing a biocompatible triazole with a PEG linker allowed different linker lengths to be investigated.…”

IU1 and enzalutamide combination yields synergistic effects on castration‐resistant prostate cancer

“…Novel AR inhibitors, such as EPI-001 and VPC-14449, could target AR beyond the ligandbinding domain, such as the N-terminal domain (NTD) or DNAbinding domain, that escape resistance from current AR competitive inhibitors. [8][9][10] Due to the dramatic increase in AR expression levels in CRPC, strategies to downregulate AR protein levels have attracted attention. AR-targeting proteolysis-targeting chimeras (PROTACs) and selective AR degraders (SARDs) can target AR protein stability and overcome resistance mechanisms, such as acquired AR mutations, the existence of AR variable splices, and overexpression of AR.…”

“…New generations of antiandrogens have been developed and applied to overcome this resistance. Novel AR inhibitors, such as EPI‐001 and VPC‐14449, could target AR beyond the ligand‐binding domain, such as the N‐terminal domain (NTD) or DNA‐binding domain, that escape resistance from current AR competitive inhibitors 8–10 . Due to the dramatic increase in AR expression levels in CRPC, strategies to downregulate AR protein levels have attracted attention.…”