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
Graphical abstract
Superimposed structures of AKR1C3 in complex with two N-aryl(amino)benzoic acid analogs, compound 1 (magenta) and compound 2 (blue).
Section snippets
Editors note
A provisional patent application based on these compounds has been submitted to the US patent office. US provisional patent applications No. 61/4754,091 filed April 13, 2011.
Acknowledgments
Supported by R01-CA90744, P30-ES013508, a Prostate Cancer Foundation Challenge Grant, and UL1RR024134 from the National Center for Research Resources (NCRR) from the National Institute of Health awarded to T.M.P. Grant GM-056838 awarded to D.W.C., and Grant F32DK089827 awarded to M.C., from the National Institutes of Health. The crystallography studies are based upon research conducted at beamline X25 and X29 of the National Synchrotron Light Source. Financial support for the National
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2019, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :Compound 1 also blocked nuclear translocation of AR at concentrations 10–40 μM, by contrast enzalutamide blocked nuclear translocation at comparable levels at a concentration of 12.5 μM, Fig. 10a. Compound 1 also caused the disappearance of AR from whole cell lysates in the presence and absence of DHT, Fig. 10b. We previously reported that compound 1 was a unique potent and selective AKR1C3 inhibitor and AR antagonist [27]. To explore the structure-activity relationships responsible for this bifunctionality we synthesized four classes of N-(naphthen-1-yl)amino-benzoates.
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These authors contributed equally to this work.