Abstract IA02: Direct targeting of the intrinsically disordered transactivation domain of androgen receptor enables transcriptome-selective pharmacology

Abstract

Androgen receptor (AR) is a therapeutic target for prostate cancer. Despite effective drugging its folded ligand-binding domain (LBD), resistance will develop by mechanisms involving reactivation of AR signaling. These mechanisms include expression of constitutively active AR that lacks LBD such as AR-V7 which fueled the discovery of inhibitors that bind to AR's N-terminal intrinsically disordered transactivation domain (TAD). AR-TAD inhibitors (ARTADIs) are unique due to the paucity of small molecule inhibitors that bind directly to intrinsically disordered TADs, which have historically been considered undruggable. Several ARTADIs have been tested in first-in human clinical trials with acceptable safety and have shown proof-of-concept for the scaffold. Over 20 years we have designed, synthesized and empirically tested over 500 ARTADIs. Leveraging this proprietary platform using cultured prostate cancer cells and multiple xenograft models we demonstrate that subtle changes in the chemical scaffold produce distinct pharmacological outputs that extend beyond binary AR antagonism. Transcriptomic analyses revealed that individual ARTADIs differentially regulate subsets of AR-responsive genes, including both androgen-induced and androgen-repressed programs, resulting in compound-specific remodeling of the AR transcriptome and signaling pathways implicated in tumor progression. These findings support a model of transcriptome-selective pharmacology. Mechanistically, these compounds differentially disrupt interactions between full-length AR or splice-variant AR-V7, and co-regulators, as revealed by rapid immunoprecipitation mass spectrometry of endogenous protein and the proximity ligation assay. This is suggestive that minor alterations in the chemical structure of ARTADIs stabilize distinct AR-TAD conformational ensembles that drive selective cofactor engagement and downstream transcriptional programs. Biophysically, several ARTADIs exhibited picomolar-to-low-nanomolar dissociation constants and covalent binding to cysteine 129. This demonstrates that intrinsically disordered transactivation domains can be targeted with affinities comparable to, or exceeding, those achieved by the LBD inhibitor enzalutamide. In vivo, representative ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. Collectively, these findings support the concept that direct targeting of the intrinsically disordered AR-TAD enables transcriptome-selective pharmacology, providing a mechanistic framework and a novel therapeutic strategy that may complement conventional AR-directed therapies. Marianne D. Sadar. Direct targeting of the intrinsically disordered transactivation domain of androgen receptor enables transcriptome-selective pharmacology [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA02.