Nuevas estrategias para la focalización de los dominios de transactivación: perspectivas del receptor de andrógenos

Mateusz Biesaga

Xavier Salvatella

Biofísica Molecular (IRB)

Transcription factors are, in theory, ideal targets for developing new therapies, as they drive the expression of genes, often those that lead to pathologies. Transactivation domains are key regions of transcription factors that provide significant contribution to their molecular functions. Pharmacological inhibition of transactivation domains could offer precise and selective way to treat many diseases, such as cancer or neurodegenerative disorders. However, development of such therapies poses a challenge as transactivation domains are largely intrinsically disordered what prevents applying classical structure-based drug design tools. In this work, we take advantage of recent developments in understanding of the structure, interactions, and functions of the transactivation domain of androgen receptor to propose inventive approaches to various drug development stages. These findings have potential to lead to new strategies to treat castration resistant prostate cancer, a disease considered a key unmet medical need. Based on the in vitro model of biomolecular condensates of androgen receptor we developed a new screening technology that allows to identify compounds modulating the biomolecular condensation propensity of the transactivation domain of androgen receptor and inhibit its function. We studied active chemical matter obtained from the developed assay in a range of experiments, validating the assay technology on multiple levels. We propose that this approach could lead to identification of new potent and selective modulators for the treatment of castration resistant prostate cancer. Furthermore, robustness, scalability, and adaptability to various proteins makes this approach a highly promising technology to unlock various targets considered “undruggable” and deliver new treatments for patients suffering from life-threatening diseases. In another attempt to develop a therapeutic strategy for the treatment of castration resistant prostate cancer we studied the interactions between the transactivation domain of androgen receptor and its molecular partner, general transcription factor IIF. Disrupting this protein-protein interaction could reduce the transcriptional activity of androgen receptor and lead to a new therapeutic opportunity for treating castration resistance prostate cancer patients. To validate this hypothesis as a viable therapeutic approach, we characterised the protein-protein interaction and developed biomimetic peptides as tool compounds to inhibit the binding. Out of two attempted approaches, one using chemical stapling, and the other one based on a highly helical scaffold, the latter showed potential to disrupt the binding. Taken together, these studies provide new insights to better understand the function and druggability of transactivation domains, using the androgen receptor as an example. We propose a new compound screening technology that can be used to identify potent inhibitors of androgen receptor. The developed screening approach has potential to be applied to other intrinsically disordered proteins beyond transactivation domains, which could lead to new therapies for key unmet medical needs.

El desarrollo de fármacos a partir de proteínas intrínsecamente desordenadas tiene el potencial de beneficiar enormemente a la sociedad, ya que estas proteínas constituyen un tercio del proteoma humano y, en muchos casos, presentan un patomecanismo que desencadena la enfermedad. De hecho, la mayoría de las oncoproteínas presentan un alto grado de desorden. Actualmente, es difícil determinar a cuántas de estas proteínas podría aplicarse la tecnología desarrollada. Sin embargo, incluso centrándose únicamente en pacientes con CPRC, el impacto de la aplicación propuesta es enorme.

Transcription Factors; Therapeutic Targets; Gene Expression; Pathologies; Transactivation Domains; Molecular Functions; Pharmacological Inhibition; Precise Therapies; Selective Therapies; Cancer; Neurodegenerative Disorders; Intrinsically Disordered Proteins; Structure-Based Drug Design; Androgen Receptor; Drug Development Stages; Castration Resistant Prostate Cancer; Unmet Medical Need; Biomolecular Condensates; Screening Technology; Modulating Compounds; Biomolecular Condensation Propensity; Assay Validation; Potent Modulators; Selective Modulators; Robustness; Scalability; Adaptability; Undruggable Targets; Life-Threatening Diseases; Therapeutic Strategy; Protein-Protein Interaction; General Transcription Factor IIF; Transcriptional Activity Reduction; Biomimetic Peptides; Tool Compounds; Chemical Stapling; Highly Helical Scaffold; Druggability; Compound Screening Technology; Potent Inhibitors.