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Pippione et al. Steroidogenic enzymes in prostate cancer

different human PCa cell lines and xenograft models in AR are classified as Selective Androgen Receptor
castrated male mice [140] ; a small molecule belonging to Degraders (SARD). A first-in-class non-steroidal
this class (EPI-506, a prodrug analogue of EPI-002 [141] ) SARD, AZD3514 (72, AstraZeneca, Macclesfield,
is now under clinical evaluation in a phase I/II study UK, Figure 17) was developed and was shown to
in men with mCRPC that have disease progression downregulate the AR [147] . AZD3514, which binds
after enzalutamide and/or abiraterone treatment the AR LBD and prevents its ligand-driven nuclear
(NCT02606123). translocation, promotes down-regulation of AR levels.
It has been clinically evaluated, but disappointingly only
The DBD is responsible for mediating interactions with moderate anti-tumour activity in patients with advanced
AREs. Encouragingly, the 3D crystal structure of the CRPC was observed; it was also shown to be poorly
rat AR DNA-binding domain has been obtained (PDB: tolerated, with nausea and vomiting being the main
1R4I) [142] . Some structures able to interact with this toxicities [148] . In the 2012, Yamashita et al. [149] identified
domain and prevent its interaction with DNA and are that ASC-J9 (73), also named as dimethylcurcumin,
shown in Figure 17. Pyrvinium (69), an antihelmintic functioned as an AR degradation enhancer for full
(and its hydrogenated analogue 1,2,3,4-tetrahydropyrv length AR and AR splicing variants. ASC-J9 is the
inium [143] ), was able to bind at the interface of the DBD first anti-AR compound discovered that selectively
[150]
dimer (inhibiting also AR splice variants lacking the degrades AR in selective cells .
LBD) and inhibit cell lines derived from both bone and
prostate [144] . Although the results are promising, some Niclosamide (74), an anthelmintic drug, has been
doubts have been expressed about the binding site on foundable to inhibit AR-V7 transcription activity and
the DBD involved in the AR inhibition by 69 [117,145] . downregulate its protein expression. Both in vitro
and in vivo PCa tumour growth were reduced upon
Insights into AR DBD inhibition were provided by treatment with 74 and it has been suggested that it acts
Li et al. [145] through the study of two molecules (70 and by promoting AR-V7 degradation via a proteasome-
[151]
71) identified through a virtual screening campaign dependent pathway . Furthermore, the combination
of niclosamide and enzalutamide resulted in significant
and subsequent medicinal chemistry investigations. inhibition of enzalutamide-resistant tumour growth,
Both compounds exhibited nanomolar potency suggesting that niclosamide enhances enzalutamide
against the AR and effectively inhibited the growth of therapy and overcomes enzalutamide resistance in
enzalutamide-resistant cells. Their binding modes were CRPC cells [151] . A phase I study of niclosamide in
corroborated by mutagenesis experiments, confirming combination with enzalutamide in men with CRPC is
interaction of these inhibitors with residues Gln592 and currently under investigation (NCT02532114).
Tyr594 of AR DBD. Compound 71 was also evaluated
in LNCaP xenografts in mice, causing comparable Also galaterone (3, Figure 4), a known CYP17
reductions in tumour volume to enzalutamide [146] . inhibitor and AR antagonist, promotes the proteasomal
degradation of both AR and its ligand-independent
In summary, much effort has gone into AR-targeted variants AR-V7 and Arv567es [152,153] .
drug design and in particular the LBD has been
pursued as a target. However, mutated forms of AR, Hydrophobic tagging technology has also been
especially constitutively active AR variants, need to employed to degrade the AR. Bradbury et al. [154]
be considered as an aspect of AR-related resistance showed that molecules containing hydrophobic
mechanisms and, for this reason, targeted with novel regions linked to small-molecule AR ligands induce
inhibitors. Accordingly, we look with particular interest AR degradation, reduce expression of AR target
to molecules targeting co-regulator binding regions genes and inhibit proliferation in androgen-dependent
and include AF-2 and BF-3 pockets (still within LBD, PCa cell lines. By appending the alkylfluoryl chain of
but their inhibition is able to overcome gain-of-function fulvestrant onto DHT, a selective SARD compound
point mutations induced by AF-2 inhibitors), the NTD was discovered. As a parallel strategy to the rational
and the DND, or molecules able to inhibit AR through design of a SARD, Gustafson et al. [155] appended an
an indirect mechanism. adamantyl moiety to the AR agonist RU59063 (75) via
a short PEG linker to create SARD279 and SARD033
Degradation of all forms of ARs are emerging as an (76 and 77, Figure 17). They found that this addition
advantageous therapeutic paradigm for the more switched the agonist into a pure antagonist capable
effective treatment of PCa in the context of AR of degrading AR protein (half-maximal degradation at
mutations that confer resistance to second-generation 1 μmol/L; maximal degradation of 95%). Moreover,
AR antagonists. The compounds able to degrade the this SARD was also able to inhibit proliferation of a

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 351