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Pippione et al. Steroidogenic enzymes in prostate cancer

of AD using NADPH as cofactor. In PCa, HSD17B3 a pharmacophore and identified a potent compound
may operate like AKR1C3 and participate in all the STX2171 [32, IC 50 ∼200 nmol/L in the whole-cell
three putative biosynthetic pathways [Figure 2]. In 293-EBNA(HSD3) assay], that had only negligible
the canonical pathway, in addition to the reduction of activity against 17β-HSD2 (the enzyme that catalyses
AD to T, it could also reduce DHEA to androstenediol, the reverse reaction) and was inactive against
while in the 5α-dione and the backdoor pathways 17β-HSD1 [83] .
it could also lead directly to DHT by reducing
5α-androstanedione or androsterone respectively STX2171 and 31 (later named STX1383) were also
[Figure 2] [24] . A better understanding of what governs tested in a hormone-dependent PCa LNCaP(HSD3)
HSD17B3 and AKR1C3 in the PCa microenvironment xenografts, which were established in castrated male
could improve efforts to more effectively target mice and using AD to stimulate tumour proliferation [83] .
these key enzymes in the steroidogenic biosynthetic Both compounds were able to inhibit the proliferation
pathway. of androgen-dependent prostate tumours (when
stimulated by AD) and to reduce but not completely
Due to the exclusive expression of HSD17B3 in the inhibit plasma T levels. An explanation of the
testes, selective inhibitors exerting effects equivalent to incomplete abolition of plasma T levels can be found
chemical castration may have potential as therapeutics in the fact that also AKR1C3, prevalently expressed in
for the treatment of PCa, and may be superior to the the prostate, performs the conversion of AD to T.
existing endocrine therapies based on a potential
reduction in off-target effects. In addition, combination In 2010, high-throughput screening led to the
with an AKR1C3-selective inhibitor could possibly lead identification of 4-methylumbelliferone (4-MU, 33) as
to more effective inhibition of the biosynthetic pathway an inhibitor of HSD17B3 [84] . The authors studied new
and subsequent AR binding. Due to HSD17B3 being 7-hydroxycoumarin derivatives of 4-MU and observed
a membrane-bound protein, a crystal structure of the most potent compounds carried substituents in
HSD17B3 is not yet available. Nonetheless, as a the 4-position. Structures 34 and 35 exhibited low
member of the SDR family, HSD17B3 could share nanomolar inhibitory activity in HeLa cells expressing
some highly conserved structural features, including human 17b-HDS3 and selectivity versus other
the Rossmann fold, the cofactor binding site and the HSD17B isoenzymes and nuclear receptors.
wide and easily accessible catalytic active site already
demonstrated for the other six members of this family. Schuster et al. [81] rationalised the potential therapeutic
opportunity of the concomitant inhibition of HSD17B3
Several research groups have reported potent and HSD17B5 because of their partly overlapping
selective steroidal and nonsteroidal inhibitors as functions. They developed pharmacophore models for
promising leads [73-76] . Recently, a review describing HSD17B types 3 and 5 and found interesting HSD17B
HSD17B3 as a target in hormone-dependent PCa 3/5 dual-targeting inhibitors with different selectivity
therapy has been published [77] , which described the profiles, although some of them were affected by
main structure, function and reporting only a few weaker off-target activity against other HSD17B
examples of steroidal and non-steroidal inhibitors of enzymes. For example, structure 36 [Figure 10] was
HSD17B3. Here we provide a discussion of the most able to reduce HSD17B3 and HSD17B5 activity by
active nonsteroidal inhibitors developed to-date. 56% and 58% at 2 µmol/L, respectively. Unfortunately,
this compound was shown to also inhibit HSD17B1
To aid structure-based drug design, some homology by 20% at the same concentration. Although research
models of HSD17B3 have been developed [78-81] . A for a dual inhibitor of HSD17B 3/5 enzymes needs
series of compounds based on the dibenzazepine deeper exploration, this approach could yield better
scaffold was discovered in 2006 and compound 29 compounds with clinical potential.
[Figure 10] was initially identified as promising hit
compound and used as a lead to discover compound In 2012, Harada et al. [85] developed a phosphate
30, which exerted picomolar activity in enzymatic as ester prodrug 37 as an orally bioavailable HSD17B3
well as cellular (stably expressing 17β-HSD3 MDA- inhibitor. The potency of the active molecule (IC 50 =
MB453 cells) assays [78] . This compound was very 12 nmol/L in HeLa cells expressing human HSD17B3)
useful in helping the design of the subsequently rendered 37 capable of reducing plasma LHRH-
discovered 17β-HSD3 inhibitors. In fact, Vicker et al. [79] induced T levels in a dose-dependent manner when
built a homology model of 17β-HSD3 and used 30, administered orally to male Sprague-Dawley rats.
as well as some structures described in Schering-
Plough patents [82] (e.g, 31, Figure 10), to construct Interestingly, some environmental chemicals like

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