90 Targeting of a Putative FKBP52 Interaction Surface On the Androgen Receptor Hormone Binding Domain

Wednesday, November 4, 2009: 11:40 AM
Kohlberg (Camino Real Hotel)
Johanny Menesis De Leon , Department of Biological Sciences, University of Texas at El Paso, El Paso, TX
Heather Balsiger, MS , Department of Biological Sciences, University of Texas at El Paso, El Paso, TX
Clementine Feau, PhD , Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN
R. Kip Guy, PhD , Medical Oncology Branch, National Cancer Institute, Bethesda, MD
Robert Fletterick, PhD , Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA
Leonard M. Neckers, PhD , Medical Oncology Branch, National Cancer Institute, Bethesda, MD
Marc B. Cox, MSPH, PhD , Department of Biological Sciences, University of Texas at El Paso, El Paso, TX
Drugs that target novel surfaces on the androgen receptor and/or novel AR regulatory mechanisms are promising alternatives for the treatment of hormone refractory prostate cancer. The 52 kDa FK506 Binding Protein (FKBP52) has been shown to be an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We have identified a surface region on the androgen receptor (AR) hormone binding domain that, when mutated, displays a greater dependence on FKBP52 for normal function. In addition, we have developed a series of small molecules that inhibit the FKBP52 regulation of AR function by binding to a novel regulatory surface on the AR hormone binding domain. This surface, termed BF3, is also hypothesized to be the FKBP52 binding domain on AR. SPR studies have confirmed that these inhibitors disrupt FKBP52 function through interaction with the AR hormone binding domain. These novel compounds do not compete with hormone for binding the hormone binding pocket, nor do they compete with coactivator peptide for binding AF2. In addition, we have shown that these compounds inhibit AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex resulting in less hormone-bound receptor in the nucleus. Finally, preliminary assays in LNCaP cells have demonstrated our novel compounds inhibit both PSA expression and androgen-dependent proliferation. In summary, we have identified a putative FKBP52 interaction surface on the AR hormone binding domain and identified a series of small molecules that inhibit AR function by targeting that surface.