Prostate cancer is the second leading cause of mortality among American men with the highest incidence rate of all cancers reported in the U.S. Male sex hormones testosterone (T) and 5α-dihydrotestosterone (5α-DHT) promote prostate cancer progression. Androgen ablation therapy (castration), which reduces the physiological amounts of the aforementioned hormones, remains the mainstay treatment strategy. After initial suppression of prostate cancer, the tumor adapts and invariably becomes resistant to conventional therapies. This therapeutic failure is marked by an emergence of a more aggressive and fatal phenotype known as castration resistant prostate cancer (CRPC).
CRPC is marked by an increase in androgen biosynthesis within the tumor, which is brought about by the upregulation of enzymes responsible for androgen synthesis. Aldo-keto reductase 1C3 (AKR1C3) is one of the steroidogenic enzymes responsible to catalyze the downstream conversion of androgen precursors to the potent androgen receptor ligands T and 5α-DHT. Expression levels of AKR1C3 were found to be significantly higher in CRPC patients, and the enzyme has been validated as a promising therapeutic target for the management of both androgen-dependent prostate cancer and CRPC.
Related, acute myeloid leukemia (AML) affects approx. 20,000 people in the U.S. (mostly pediatric and geriatric) and is characterized by a differentiation arrest and proliferation of naïve precursor cells of myelocytic lineage in the bone marrow. Chemotherapy with anthracyclines (e.g., daunorubicin) is the preferred clinical treatment strategy for managing AML. They are, however, transformed into inactive hydroxy metabolites upon exposure to AKR1C3, which imparts resistance to these chemotherapeutics. AKR1C3 is also known to be an important regulator of myeloid cell proliferation and differentiation—important facets in leukemias, with the 1C3 isoform overexpressed in a range of leukemia cell lines. Also known as prostaglandin F synthase (PGFS), the enzyme catalyzes the formation of PGF2α prostanoids that exert a pro-proliferative influence on myeloblasts and myelocytes. Such activities make AKR1C3 an attractive target for managing AML resistance and disease progression, much like this enzyme's potential for the treatment of CRPC.
Applying the medicinal chemistry technique of structure-activity relationship optimization, we synthesized a library of compounds as potent and selective AKR1C3 inhibitors based on a natural product scaffold. The lead compounds were evaluated for antiproliferative activity in in vitro models of CRPC and AML. Among CRPC cell lines, AKR1C3 inhibitors potently reduced the cellular proliferation and induced a strong sensitization effect toward the action of the clinically employed chemotherapeutic enzalutamide. A very high degree of drug synergism was observed wherein an approximate 40-fold reduction in the dosing of enzalutamide was achievable. AML cell models also demonstrated a high degree of synergistic effect (up to 6-fold dose reduction) upon combination treatment of AKR1C3 inhibitors with the clinical chemotherapeutics etoposide and daunorubicin.
Since AKR1C3 is responsible for the pathogenesis and progression of CRPC and AML, use of selective AKR1C3 enzyme inhibitors could offer new therapeutic avenues to improve disease prognosis by combating therapeutic resistance, reducing the adverse effects of anti-cancer agents used in the clinic and consequently improving patient compliance and survival.