title: Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets.
abstract: Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN 38163, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Duke
authors.forename: Amanda
authors.initials: A
authors.lastname: Jones
authors.forename: Casey E
authors.initials: CE
authors.lastname: Bohl
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000728:Androgens / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D011944:Receptors, Androgen