Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Abstract

Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists

“…1 The initiation and progression throughout the different stages of prostate cancer (PC) is uniquely dependent on the androgen receptor (AR) signalling pathway. 2,3 Androgen receptor (AR), like other members of the nuclear receptor family, is comprised of three main functional domains: a variable N-terminal domain, a highly conserved DNA-binding domain (DBD) and a conserved ligand binding domain (LBD). 4 Binding of endogenous hormones; testosterone and dihydrotestosterone (DHT) to the LBD induces conformational changes in the AR that results in its translocation into the nucleus, interaction with DNA, and modulation of specific gene transcription (e.g.…”

Exploration of [2 + 2 + 2] cyclotrimerisation methodology to prepare tetrahydroisoquinoline-based compounds with potential aldo–keto reductase 1C3 target affinity

“…In the steroid biosynthesis pathway, the aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme that is known to catalyse transformation of the hormone precursors androstenedione and androsterone to highly active testosterone and dihydrotestosterone (DHT) respectively, which is linked with prostate cancer cell proliferation. 2 Much AKR1C3 inhibitor research has been focused on medroxyprogesterone acetate (MPA), steroidal lactones, cinnamic acids, flavonoids and nonsteroidal anti-inflammatory drugs (NSAIDs) 3 while new potent and selective 1,3,5-metasubstituted retroinverted amides show promise for lead optimisation. 4 Our interest in novel drug design approaches [5][6][7] has recently led to the discovery of benzoisoxazole, hydroxytriazole and hydroxyfurazan NSAIDs as potent and selective AKR1C3 inhibitors by application of a bioisosteric scaffold hopping approach.…”

Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid

“…[2] AKR1C3 may provide a mechanism to divert traces of androgens that remain after androgen deprivation therapy (ADT) to the potent androgen receptor (AR) ligand 5α-dihydrotesterone (DHT). [3] Besides evidence that AR mutations, splice variants and increased copy number represent putative mechanisms of resistance to therapy, [4][5][6][7] AKR1C3 has also been discovered to play a role in resistance to pharmacological [6] and radiation [8] therapy. Potential clinical use of AKR1C3 inhibitors has been demonstrated as in the case of indomethacin, a potent but unselective AKR1C3 inhibitor able to circumvent resistance to both abiraterone (ABI) [9] and enzalutamide (ENZA) [10] (Figure 1).…”