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Pippione et al. Steroidogenic enzymes in prostate cancer

Figure 5: Design strategy of metal-binding inhibitors of CYP17A1

steroidal compounds selective for CYP17A1 [42] . This these analogues, the most potent compound was 9
second study afforded the discovery of compound 7. In [Figure 5], showing 1.5 fold greater potency against
vitro assays in human H295R cells demonstrated that rat and human CYP17A1 protein than abiraterone. In
compounds 6 and 7 selectively inhibited CYP17A1 NCI-H295R cells, the inhibitory effect of compound
17α-hydroxylase (IC 50 values of 830 and 52 nmol/L, 9 on T production was also more potent than that of
respectively) and 17,20-lyase (IC 50 values of 94 and abiraterone at a concentration of 1 µmol/L. Further, it
7.4 nmol/L, respectively) activities. Strong coordination was shown that 9 reduced plasma T level in a dose-
of compound 7 to the haem iron is likely to be dependent manner in Sprague-Dawley rats and may
responsible for inhibition of both reactions. These be a lead compound for further preclinical studies.
compounds do not bind selected drug-metabolising
cytochrome P450 enzymes or the steroidogenic AKR1C3
CYP21A2, suggesting a reduced risk for undesirable AKR1C3, also named HSD17B5, is a soluble
side effects, especially on the corticosteroid production, enzyme member of the aldo-ketoreductase family,
consistent with data observed in vitro. Taken together, highly expressed in testes and extragonadal tissues
these data recommend compounds 6 and 7 as such as basal cells of the prostate, adrenals and
promising tools for the continued development of new liver. Principally, it catalyses the NADPH dependent
drugs against PCa [42] . reduction of AD to T but is known to be involved
with 3α-HSD, 20α-HSD, dihydrodiol dehydrogenase
Structural analysis of the reported CYP17A1 inhibitors and prostaglandin synthase activities [44] . Compared
reveals that most of the inhibitors consist of two to other HSD17B isoforms, AKR1C3 was the most
structural features. One is the metal-binding group that abundant isoform expressed in several PCa cells
binds to the haem iron and the second is the scaffold that and its expression is upregulated in CRPC [Table 2].
binds to the substrate pocket of CYP17A1. Based on this AKR1C3 plays a key role in producing DHT in each of
the three pathways, since it can lead to the synthesis
[43]
observation, recently Wang et al. conducted a screen of DHT starting from AD and DHEA in the canonical
of compounds from an in-house metalloenzyme pathway, from 5α-androstanedione in the 5α-dione
inhibitor library and identified compound 8 [Figure 5] pathway, and from androsterone in the backdoor
to selectively inhibit rat CYP17A1 lyase with sub pathway [Figure 2]. Elevated levels of expression of
micromolar activity. AKR1C3 in CPRC provide a mechanism to divert trace
androgens that remain after ADT to the potent AR
A preliminary modelling study indicated that compound ligand DHT via these three pathways intratumourally
8 could fit nicely into the CYP17A1 binding pocket and may indirectly also impact on CYP17A1 inhibitor or
and maintain the key interactions with the residues AR antagonist resistance mechanisms . Furthermore,
[9]
of CYP17A1. The nitrogen of the pyridine and the AKR1C3 has also been discovered to play a role in
tetrahydro-β-carboline core formed a coordination resistance to radiation therapy [45] .
bond and hydrophobic interactions with haem group
(iron atom) and hydrophobic pocket respectively. Because of its structural differences with HSD17B3,
Since authors showed that there was unfilled space an enzyme belonging to SDR family and catalysing the
on the pyridine part in the active site cavity, they same reaction of AKR1C3 in testis [46] , AKR1C3 could
introduced substituent onto the pyridine ring to occupy be a good target for selective inhibition.
this space and enhance the potency. These efforts led
to the design and synthesis of a series of compounds At present, there are more than 40 crystal structures
bearing different substituted pyridine and pyrimidine of AKR1C3 in the 2017 International Union of
moieties and evaluated their CYP17A1 activity. Of Crystallography Protein Data Bank. The first crystal

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