4DBS

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 3'-[(4-nitronaphthalen-1-yl)amino]benzoic acid

Summary for 4DBS

• Entry DOI: 10.2210/pdb4dbs/pdb
• Related: 4DBU
• Descriptor: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-[(4-nitronaphthalen-1-yl)amino]benzoic acid, ... (4 entities in total)
• Functional Keywords: castrate resistant prostate cancer, akr1c3 selective inhibitor, tim barrel, steroid metabolism, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P42330
• Total number of polymer chains: 2
• Total formula weight: 76512.39

Authors

Chen, M.,Christianson, D.W.,Winkler, J.D.,Penning, T.M. (deposition date: 2012-01-16, release date: 2012-03-28, Last modification date: 2023-09-13)

Primary citation

Chen, M.,Adeniji, A.O.,Twenter, B.M.,Winkler, J.D.,Christianson, D.W.,Penning, T.M.
Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer.
Bioorg.Med.Chem.Lett., 22:3492-3497, 2012

PubMed Abstract: Castrate resistant prostate cancer (CRPC) is associated with increased androgen receptor (AR) signaling often brought about by elevated intratumoral androgen biosynthesis and AR amplification. Inhibition of androgen biosynthesis and/or AR antagonism should be efficacious in the treatment of CRPC. AKR1C3 catalyzes the formation of potent AR ligands from inactive precursors and is one of the most upregulated genes in CRPC. AKR1C3 inhibitors should not inhibit the related isoforms, AKR1C1 and AKR1C2 that are involved in 5α-dihydrotestosterone inactivation in the prostate. We have previously developed a series of flufenamic acid analogs as potent and selective AKR1C3 inhibitors [Adeniji, A. O. et al., J. Med. Chem.2012, 55, 2311]. Here we report the X-ray crystal structure of one lead compound 3-((4-(trifluoromethyl)phenyl) amino)benzoic acid (1) in complex with AKR1C3. Compound 1 adopts a similar binding orientation as flufenamic acid, however, its phenylamino ring projects deeper into a subpocket and confers selectivity over the other AKR1C isoforms. We exploited the observation that some flufenamic acid analogs also act as AR antagonists and synthesized a second generation inhibitor, 3-((4-nitronaphthalen-1-yl)amino)benzoic acid (2). Compound 2 retained nanomolar potency and selective inhibition of AKR1C3 but also acted as an AR antagonist. It inhibited 5α-dihydrotestosterone stimulated AR reporter gene activity with an IC(50)=4.7 μM and produced a concentration dependent reduction in androgen receptor levels in prostate cancer cells. The in vitro and cell-based effects of compound 2 make it a promising lead for development of dual acting agent for CRPC. To illuminate the structural basis of AKR1C3 inhibition, we also report the crystal structure of the AKR1C3·NADP(+)·2 complex, which shows that compound 2 forms a unique double-decker structure with AKR1C3.

PubMed: 22507964
DOI: 10.1016/j.bmcl.2012.03.085

Experimental method

X-RAY DIFFRACTION (1.852 Å)