Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): Overview and structural insights

doi:10.1016/j.jsbmb.2010.11.004

The Journal of Steroid Biochemistry and Molecular Biology

Volume 125, Issues 1–2, May 2011, Pages 95-104

https://doi.org/10.1016/j.jsbmb.2010.11.004 Get rights and content

Abstract

There is considerable interest in the development of an inhibitor of aldo–keto reductase (AKR) 1C3 (type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase) as a potential therapeutic for both hormone-dependent and hormone-independent cancers. AKR1C3 catalyzes the reduction of 4-androstene-3,17-dione to testosterone and estrone to 17β-estradiol in target tissues, which will promote the proliferation of hormone dependent prostate and breast cancers, respectively. AKR1C3 also catalyzes the reduction of prostaglandin (PG) H₂ to PGF_2α and PGD₂ to 9α,11β-PGF₂, which will limit the formation of anti-proliferative prostaglandins, including 15-deoxy-Δ^12,14-PGJ₂, and contribute to proliferative signaling. AKR1C3 is overexpressed in a wide variety of cancers, including breast and prostate cancer. An inhibitor of AKR1C3 should not inhibit the closely related isoforms AKR1C1 and AKR1C2, as they are involved in other key steroid hormone biotransformations in target tissues. Several structural leads have been explored as inhibitors of AKR1C3, including non-steroidal anti-inflammatory drugs, steroid hormone analogues, flavonoids, cyclopentanes, and benzodiazepines. Inspection of the available crystal structures of AKR1C3 with multiple ligands bound, along with the crystal structures of the other AKR1C isoforms, provides a structural basis for the rational design of isoform specific inhibitors of AKR1C3. We find that there are subpockets involved in ligand binding that are considerably different in AKR1C3 relative to the closely related AKR1C1 or AKR1C2 isoforms. These pockets can be used to further improve the binding affinity and selectivity of the currently available AKR1C3 inhibitors.

Article from the special issue on Targeted Inhibitors.

Research highlights

► AKR1C3 produces steroids and prostaglandins for receptor mediated growth. ► AKR1C3 inhibition is desirable for hormone dependent and independent cancers. ► NSAIDs, steroids, flavonoids, cyclopentanes, and benzodiazepines inhibit AKR1C3. ► Crystal structures identify subpockets for rational design of AKR1C3 inhibitors. ► Differences in AKR1C subpockets can be exploited for selective inhibition.

Section snippets

Rationale for AKR1C3 inhibition

Aldo–keto reductase (AKR) 1C3²

Overview of AKR1C3 inhibitors

AKR1C3 is inhibited by several structural classes of compounds. Structures of representative compounds from each known class of inhibitors and their potency towards AKR1C isoforms are shown in Fig. 2. Although there is significant structural diversity in the types of compounds that inhibit AKR1C3, they all contain one or more rings and at least one carbonyl group. Interestingly, many of the compounds that inhibit AKR1C3 have already been described as being effective in the chemoprevention of

Available crystal structures

Crystal structures of the four human AKR1C enzymes have been actively pursued by several groups. Ten crystal structures of different AKR1C3 ternary complexes have been deposited into the Protein Data Bank (Table 1) [48], [55], [56], [57], [58], [59]. These structures have provided a strong basis for understanding the activities of existing inhibitors and for rational design of AKR1C3 inhibitors with better selectivity and potency.

Characteristics of the AKR1C3 substrate binding site

In the ten crystal structures of AKR1C3, the enzyme is complexed

Conclusion

Accumulating evidence suggests that AKR1C3 plays an important role in the hormone-dependent and hormone-independent cancers. This has led to the increasing interest in the development of AKR1C3 inhibitors. However, selective inhibition is critical, since the other closely related AKR1C enzymes are also ubiquitously expressed and involved in important steroid hormone biotransformation reactions. Among the compounds that have been examined for AKR1C3 inhibition, some inhibitors (e.g. CBM)

Acknowledgement

Funding: Supported by R01-CA90744 and P30-ES013508 awarded to T.M.P. M.C.B. was funded by NIH training grants T32-DK007314-25 and T32-HD007305-22. Y.J. was also funded by a FOCUS-Junior Investigator Award from the Kynett Foundation.

References (62)

M.C. Byrns et al.
Aldo–keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer
J. Steroid Biochem. Mol. Biol.
(2010)
K.K. Sharma et al.
Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid tissues
Mol. Cell. Endocrinol.
(2006)
T. Suzuki-Yamamoto et al.
cDNA cloning, expression and characterization of human prostaglandin F synthase
FEBS Lett.
(1999)
N Koda et al.
Synthesis of prostaglandin F ethanolamide by prostaglandin F synthase and identification of bimatoprost as a potent inhibitor of the enzyme: new enzyme assay method using LC/ESI/MS
Arch. Biochem. Biophys.
(2004)
T.M. Penning et al.
Pre-receptor regulation of the androgen receptor
Mol. Cell. Endocrinol.
(2008)
T. Smuc et al.
Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer
Mol. Cell. Endocrinol.
(2009)
H.-K. Lin et al.
Characterization of a monoclonal antibody for human aldo–keto reductase AKR1C3 (type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate
Steroids
(2004)
T. Smuc et al.
Disturbed estrogen and progesterone action in ovarian endometriosis
Mol. Cell. Endocrinol.
(2009)
J.A. Loudon et al.
Prostaglandin inhibitors in preterm labour
Best Pract. Res. Clin. Obstet. Gynaecol.
(2003)
M.C. Byrns et al.
An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo–keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies
Biochem. Pharmacol.
(2008)

M.J. Reginato et al.

Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor γ

J. Biol. Chem.

(1998)

S.A. Kliewer et al.

A prostaglandin J₂ metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation

Cell

(1995)

A. Janssen et al.

Evidence of COX-2 independent induction of apoptosis and cell cycle block in human colon carcinoma cells after S- or R-ibuprofen treatment

Eur. J. Pharmacol.

(2006)

M.C. Byrns et al.

Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs

Chem. Biol. Interact.

(2009)

Y. Higaki et al.

Selective and potent inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone

Chem. Biol. Interact.

(2003)

P. Bydal et al.

Steroidal lactones as inhibitors of 17β-hydroxysteroid dehydrogenase type 5: chemical synthesis, enzyme inhibitory activity, and assessment of estrogenic and androgenic activities

Eur. J. Med. Chem.

(2009)

W. Qiu et al.

Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17β-hydroxysteroid dehydrogenase

J. Biol. Chem.

(2007)

L. Skarydova et al.

AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids

Chem. Biol. Interact.

(2009)

P. Brozic et al.

Cinnamic acids as new inhibitors of 17β-hydroxysteroid dehydrogenase type 5 (AKR1C3)

Mol. Cell. Endocrinol.

(2006)

B. Stefane et al.

New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3

Eur. J. Med. Chem.

(2009)

M.J. Bennett et al.

Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP⁺ bound to 3α-hydroxysteroid/dihydrodiol dehydrogenase

Structure

(1997)

Y. Jin et al.

Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences

Steroids

(2006)

J.F. Couture et al.

Human 20α-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids

J. Mol. Biol.

(2003)

T.M. Penning, Human hydroxysteroid dehydrogenases and pre-receptor regulation: insights into inhibitor design and...

S. Marchais-Oberwinkler, C. Hennl, G. Möller, T. Klein, M. Negri, A. Oster, A. Spadaro, R. Werth, M. Wetzel, K. Xu, M....

D. Poirier, Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: key tools...

I. Dufort et al.

Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase

Endocrinology

(1999)

K. Matsuura et al.

Identification of a principal mRNA species for human 3α-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D₂ 11-ketoreductase activity

J. Biochem.

(1998)

H.N. Jabbour et al.

A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F_2α synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway

Endocrinology

(2005)

D.M. Ray et al.

The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxy-Δ^12,14-prostaglandin J₂ and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms

J. Immunol.

(2006)

A.R. Diers et al.

Modulation of mammary cell migration by 15-deoxy-Δ^12,14-prostaglandin J₂: implications for anti-metastatic therapy

Biochem. J.

(2010)

Cited by (107)

Inhibition of AKR1Cs by liquiritigenin and the structural basis
2023, Chemico-Biological Interactions
In vivo and in vitro studies have confirmed that liquiritigenin (LQ), the primary active component of licorice, acts as an antitumor agent. However, how LQ diminishes or inhibits tumor growth is not fully understood. Here, we report the enzymatic inhibition of LQ and six other flavanone analogues towards AKR1Cs (AKR1C1, AKR1C2 and AKR1C3), which are involved in prostate cancer, breast cancer, and resistance of anticancer drugs. Crystallographic studies revealed AKR1C3 inhibition of LQ is related to its complementarity with the active site and the hydrogen bonds net in the catalytic site formed through C₇–OH, aided by its nonplanar and compact structure due to the saturation of the C₂C₃ double bond. Comparison of the LQ conformations in the structures of AKR1C1 and AKR1C3 revealed the induced-fit conformation changes, which explains the lack of isoform selectivity of LQ. Our findings will be helpful for better understanding the antitumor effects of LQ on hormonally dependent cancers and the rational design of selective AKR1Cs inhibitors.
Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer
2023, European Journal of Medicinal Chemistry
Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the “gold standard” for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19–1035) exhibits an IC₅₀ value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.
History of androgens and androgen action
2022, Best Practice and Research: Clinical Endocrinology and Metabolism
Overview of human 20 alpha-hydroxysteroid dehydrogenase (AKR1C1): Functions, regulation, and structural insights of inhibitors
2022, Chemico-Biological Interactions
Human aldo-keto reductase family 1C1 (AKR1C1) is an important enzyme involved in human hormone metabolism, which is mainly responsible for the metabolism of progesterone in the human body. AKR1C1 is highly expressed and has an important relationship with the occurrence and development of various diseases, especially some cancers related to hormone metabolism. Nowadays, many inhibitors against AKR1C1 have been discovered, including some synthetic compounds and natural products, which have certain inhibitory activity against AKR1C1 at the target level. Here we briefly reviewed the physiological and pathological functions of AKR1C1 and the relationship with the disease, and then summarized the development of AKR1C1 inhibitors, elucidated the interaction between inhibitors and AKR1C1 through molecular docking results and existing co-crystal structures. Finally, we discussed the design ideals of selective AKR1C1 inhibitors from the perspective of AKR1C1 structure, discussed the prospects of AKR1C1 in the treatment of human diseases in terms of biomarkers, pre-receptor regulation and single nucleotide polymorphisms, aiming to provide new ideas for drug research targeting AKR1C1.
Significance of aldo-keto reductase 1C3 and ATP-binding cassette transporter B1 in gain of irinotecan resistance in colon cancer cells
2020, Chemico-Biological Interactions
Irinotecan (CPT11) is widely prescribed for treatment of various intractable cancers such as advanced and metastatic colon cancer cells, but its continuous treatment promotes the resistance development. In this study, we established CPT11-resistant variants of three human colon cancer (DLD1, RKO and LoVo) cell lines, and found that gain of the resistance elicited an up-regulation of aldo-keto reductase (AKR) 1C3 in the cells. Additionally, the sensitivity to CPT11 toxicity was decreased and increased by overexpression and knockdown, respectively, of the enzyme. Moreover, the resistant cells suppressed formation of reactive 4-hydroxy-2-nonenal by CPT11 treatment, and the suppressive effect was almost completely abolished by addition of an AKR1C3 inhibitor. These results suggest that up-regulated AKR1C3 contributes to promotion of the chemoresistance by detoxifying the reactive aldehyde. Western blot and real-time polymerase-chain reaction analyses and ATP-binding cassette (ABC) B1-functional assay revealed that, among three ABC transporters, ABCB1 was the most highly up-regulated by development of the CPT11 resistance, inferring a significant contribution of pregnane-X receptor-dependent signaling to the ABCB1 up-regulation. The combined treatment with inhibitors of AKR1C3 and ABCB1 potently sensitized the resistant cells to CPT11 and its active metabolite SN38. Taken together, our results suggest that combination of AKR1C3 and ABCB1 inhibitors is effective as adjuvant therapy to enhance CPT11 sensitivity of intractable colon cancer cells.
Role of arachidonic acid metabolism in intervertebral disc degeneration: identification of potential biomarkers and therapeutic targets via multi-omics analysis and artificial intelligence strategies
2023, Lipids in Health and Disease

View all citing articles on Scopus

¹: These authors contributed equally to this article.

View full text

ReviewInhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): Overview and structural insights

Abstract

Research highlights

Section snippets

Rationale for AKR1C3 inhibition

Overview of AKR1C3 inhibitors

Available crystal structures

Characteristics of the AKR1C3 substrate binding site

Conclusion

Acknowledgement

J. Steroid Biochem. Mol. Biol.

Mol. Cell. Endocrinol.

FEBS Lett.

Arch. Biochem. Biophys.

Mol. Cell. Endocrinol.

Mol. Cell. Endocrinol.

Steroids

Mol. Cell. Endocrinol.

Best Pract. Res. Clin. Obstet. Gynaecol.

Biochem. Pharmacol.

J. Biol. Chem.

Cell

Eur. J. Pharmacol.

Chem. Biol. Interact.

Chem. Biol. Interact.

Eur. J. Med. Chem.

J. Biol. Chem.

Chem. Biol. Interact.

Mol. Cell. Endocrinol.

Eur. J. Med. Chem.

Structure

Steroids

J. Mol. Biol.

Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase

Endocrinology

Identification of a principal mRNA species for human 3α-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity

J. Biochem.

A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2α synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway

Endocrinology

The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxy-Δ12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms

J. Immunol.

Modulation of mammary cell migration by 15-deoxy-Δ12,14-prostaglandin J2: implications for anti-metastatic therapy

Biochem. J.

Review
Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): Overview and structural insights

Identification of a principal mRNA species for human 3α-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D₂ 11-ketoreductase activity

A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F_2α synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway

The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxy-Δ^12,14-prostaglandin J₂ and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms

Modulation of mammary cell migration by 15-deoxy-Δ^12,14-prostaglandin J₂: implications for anti-metastatic therapy