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Novel AKR1C3 Inhibitors in Cancer

Inhibitors and tools to block the local formation of steroid hormones in hormone-dependent malignancies of the prostate, breast and endometrium

Problem:

As proof-of-principle, Dr. Penning has focused attention on castration resistant prostate cancer (CRPC). CRPC is uniformly fatal and accounts for 30,000 deaths annually in the US alone. Advanced prostate cancer is treated with hormone ablative therapy (chemical or surgical castration), which results in an initial period of tumor regression.

Invariably the tumor reappears and remains androgen driven despite castrate levels of circulating androgens. This occurs because the tumor adapts to make its own androgens and because of adaptive changes in the androgen receptor. These two mechanisms are targeted by abiraterone acetate (Zytiga®) and enzalutamide (Xtandi®), respectively.

Each agent only prolongs survival by 3- 4 months and resistance to these agents occurs. Thus, better agents are sorely needed.

Solution:

Dr. Penning’s team has identified AKR1C3 (17β-hydroxysteroid dehydrogenase type 5) as a unique target in CRPC. All pathways to the most potent androgen 5α-dihydrotestosterone proceed through AKR1C3. AKR1C3 is highly over expressed in CRPC and it is up-regulated upon androgen deprivation, in cell lines, in tumor xenografts, and in metastatic tissues in prostate cancer patients. Genetic manipulation (knock down approaches) and pharmacological inhibition shows that AKR1C3 is necessary and sufficient to drive androgen dependent gene expression and cell proliferation.

Recent work has identified nonsteroidal anti-inflammatory drugs (NSAIDs) as potent but non-specific inhibitors of AKR1C3, identifying existing drugs that could be redesigned as AKR1C3 inhibitors. To this end four different classes of SIMs have been developed as lead therapeutic agents:

- [Class 1] N-phenylaminobenzoates;
- [Class 2] R-profens;
- [Class 3] indomethacin analogs; and
- [Class 4] N-naphthylaminobenzoates.

Compounds in all four classes:

- have nanomolar potency for AKR1C3 in in vitro assays;
- are selective and do not inhibit any of the other nine human AKRs;
- they do not inhibit the NSAID targets COX-1 and COX-2;
- they block testosterone biosynthesis in prostate cancer cell lines that over express AKR1C3; and
- they block androgen dependent gene expression e.g. PSA.

Compounds in Class 4 have the unexpected property of acting as AKR1C3 inhibitors and as androgen receptor antagonists making them bifunctional. Bifunctional agents have the potential to be superior to giving abiraterone and enzalutamide in combination.

Technology Overview:

Standard treatment of care for hormone-dependent tumors utilizes hormone ablative therapies. These agents non-discriminately block the action of estrogens and androgens and have untoward side effects. Additionally, patients develop resistance to these agents quite frequently. Dr. Penning has identified enzymes that belong to the aldo-keto reductase (AKR) superfamily that are required for hormone synthesis in a tumor-specific manner. His lab has developed AKR inhibitors that could block steroid hormone synthesis within these tumors with precision.