OR04-04 Androgen Receptor Multimerization Modulators

Abstract Disclosure: E. Estebanez-Perpina: None. Alba Jiménez-Panizo1,2#, Andrea Alegre-Martí1#, Inés Montoya-Novoa1, José LuisGardeazábal-Torbado1, Montserrat Abella1, Adrián Martínez-Tébar3,Juan Fernández-Recio2, Jun Xu4, Arnold T. Hagler5, Álvaro Aytes3Pablo Fuentes-Prior1*, and Eva Estébanez-Perpiñá1*.1Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute ofBiomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028Barcelona, Spain.2Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC, Universidad de La Rioja, Gobiernode La Rioja, 26007 Logroño, Spain.3Programs of Molecular Mechanisms and Experimental Therapeutics in Oncology(ONCOBell) and Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology,Bellvitge Institute for Biomedical Research, 08908 Barcelona, Spain.4United Lab for Ferroptosis Research, The Chinese University of Hong Kong and CinaneoPharm. Shenzhen 518000, China.5Department of Chemistry, University of Massachusetts, Amherst, MA, USA. Androgen receptor mediates as a transcription factor the activity of androgenichormones and it is both the major driver as well as the main drug target fortherapeutics against prostate cancer. AR is also implicated in the aetiology of twodistinct rare diseases, namely androgen insensitivity syndromes and spinal andbulbar muscular atrophy. Due to its modular and flexible structure, AR has beenshown to display different conformations using X-ray crystallography and cryo-electron microscopy at medium/low resolution. Further, AR dimerization andoligomerization state exhibits notable differences with other related steroid receptorsof the same superfamily. We show that the non-canonical dimerization interface is adruggable allosteric target susceptible of pharmacological treatment as we previouslyshowed for the BF-3 surface, both located at different ends of the domain. Further,the dimerization site and the BF-3 pocket are not only allosterically linked but thelatter is a tetramerization interface. We have discovered a series of low molecularweight ligands that bind weakly either to AR dimerization site, BF-3 multimerizationsite or both. We propose dimerization and tetramerization modulators of AR asalternative ways to tackle AR-linked diseases. Presentation: Saturday, July 12, 2025