Abstract
These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation.
Highlights
We propose that androgen receptor (AR)/AR-V7 and mitogen-activated protein kinase-interacting kinases 1 and 2 (Mnk1/2) degraders could be effective in prostate cancer patients with upregulation of AR/AR-V7 and Mnk1/2 proteins, which currently represents a pressing therapeutic challenge [19,20,28,29,30,31]
Thereafter, we demonstrated that our lead next generation galeterone analogs (NGGAs) exert strong anti-migratory and antiinvasive activities in the prostate cancer (PC)-3 cell line which are noted for their high migratory and invasive potential
We have demonstrated that Gal and the NGGAs target the androgen receptor and Mnk1/2-eukaryotic initiation factor 4E (eIF4E) signaling pathways and that the NGGAs are more effective than Gal [8,9,11]
Summary
Galeterone (Gal; Figure 1), a steroidal molecule designed by our group to inhibit 17αGaleterone (Gal; Figure1), a akey steroidal designed bypathway our group hydroxylase/17.20-lyase (CYP17), enzymemolecule in the steroidogenic that to lie inhibit at the17α-hydroxylase/17.20-lyase (CYP17), a key enzyme in the steroidogenic pathway that lie at the crossroads of androgen and corticoid biosynthesis was found to disrupt the androgen receptor (AR)crossroads of androgen and corticoid biosynthesis was found to disrupt the androgen receptor signaling pathway via inhibition of androgen synthesis (CYP 17 inhibition; reviewed in [1]), AR (AR)signaling pathway via inhibition androgen synthesis (CYP 17through inhibition; reviewed in [1]), antagonism, and AR degradation [1,2,3].ofGal progressed successfully Phase 1 and PhaseAR antagonism, and degradation [1,2,3].Gal progressed successfully through Phase andPhase clinical trials in men with castration-resistant prostate cancer (CRPC) but failed in the pivotal phase clinical trials in [4,5,6]. Galeterone (Gal; Figure 1), a steroidal molecule designed by our group to inhibit 17αGaleterone 1), a akey steroidal designed bypathway our group hydroxylase/17.20-lyase (CYP17), enzymemolecule in the steroidogenic that to lie inhibit at the. 17α-hydroxylase/17.20-lyase (CYP17), a key enzyme in the steroidogenic pathway that lie at the crossroads of androgen and corticoid biosynthesis was found to disrupt the androgen receptor (AR). Crossroads of androgen and corticoid biosynthesis was found to disrupt the androgen receptor signaling pathway via inhibition of androgen synthesis (CYP 17 inhibition; reviewed in [1]), AR (AR). Signaling pathway via inhibition androgen synthesis (CYP 17through inhibition; reviewed in [1]), antagonism, and AR degradation [1,2,3].ofGal progressed successfully Phase 1 and Phase.
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