Title: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.
Authors: Liedtke, Andy J; Adeniji, Adegoke O; Chen, Mo; Byrns, Michael C; Jin, Yi; Christianson, David W; Marnett, Lawrence J; Penning, Trevor M
Published In J Med Chem, (2013 Mar 28)
Abstract: Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP(+)·2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.
PubMed ID: 23432095
MeSH Terms: 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors*; 3-Hydroxysteroid Dehydrogenases/chemistry; 3-Hydroxysteroid Dehydrogenases/metabolism; Aldo-Keto Reductase Family 1 Member C3; Catalytic Domain; Enzyme Inhibitors/chemistry*; Enzyme Inhibitors/pharmacology*; Genes, Reporter/genetics; HeLa Cells; Humans; Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors*; Hydroxyprostaglandin Dehydrogenases/chemistry; Hydroxyprostaglandin Dehydrogenases/metabolism; Indomethacin/analogs & derivatives*; Indomethacin/pharmacology*; Male; Models, Molecular; Neoplasm Metastasis; Orchiectomy*; Prostatic Neoplasms/enzymology*; Prostatic Neoplasms/pathology; Prostatic Neoplasms/surgery; Receptors, Androgen/genetics; Substrate Specificity