Researchers at UBC and BC Cancer have published results demonstrating that a new class of androgen receptor TAD inhibitors (ARTADIs), particularly lead compound BU3 12, can achieve up to one million fold stronger binding to the intrinsically disordered N terminal domain of the…
For twenty years, the pharmaceutical industry told Marianne Sadar she was chasing a ghost.
The proteins she wanted to hit — intrinsically disordered proteins, or IDPs — had no fixed shape. They twisted and flexed as they performed their biological functions, and the entire edifice of modern drug discovery was built on the opposite assumption: that targets needed rigid, lock-and-key structures to be drugged. In 2003, when Sadar's lab at the University of British Columbia began screening compounds against the androgen receptor's disordered region, the field had already decided that target was a dead end.
It was not. On April 27th, a team from UBC and BC Cancer published results in Nature Signal Transduction and Targeted Therapy showing that a new generation of compounds — ARTADIs, for androgen receptor TAD inhibitors — could bind their target with up to a million times the strength of previous molecules. In animal models, the best candidates outperformed enzalutamide, the standard prostate cancer drug, even in the presence of androgens that drive treatment resistance. The work was not a breakthrough so much as a culmination: twenty years of accumulated evidence that the field had been wrong about what was undruggable.
The comeback angle is not academic. Six weeks before this paper appeared, ESSA Pharma discontinued development of masofaniten (EPI-7386), an earlier ARTADI that had reached Phase 2 trials. The combination of masofaniten and enzalutamide failed a futility analysis: patients receiving both drugs showed a 64% PSA90 response rate, compared to 73% for enzalutamide alone. The first ARTADI to reach late-stage trials did not work.
That failure sits uncomfortably alongside the new paper's optimism. Masofaniten belongs to a chemical family — the tricyclic anitens — that the new Nature paper explicitly distinguishes from its lead compounds. BU3-12, the selected lead from the UBC team, retains a chlorohydrin group that the paper's structure-activity analysis identifies as generally important for on-target activity. Masofaniten lacks this group. Whether that chemical difference translates to a real clinical advantage is unproven.
The androgen receptor matters because it drives most prostate cancers, even after hormone therapy stops working. Current drugs target its folded ligand-binding domain — but resistance evolves, via mutations in that same domain or through splice variants like AR-V7 that simply delete the target site entirely. ARTADIs hit a different region: the intrinsically disordered N-terminal domain that no current therapy reaches. Resistance mechanisms that defeat enzalutamide do not automatically defeat an ARTADI.
Raymond Andersen, a UBC chemist and co-corresponding author, put it plainly: "We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working." The caveat is that this happened in mice.
The broader platform claim is harder to dismiss. IDPs make up roughly 40% of the human proteome and are implicated in cancers, neurodegenerative diseases, and autoimmune conditions. If even a fraction of them prove tractable to the approach Sadar's team has refined over two decades, the druggable universe expands significantly. Several pharmaceutical groups are watching BU3-12's trajectory. The chlorohydrin question will determine whether they place bets.
Notebook: ESSA Pharma's masofaniten was developed by the same Sadar lab group that produced the new paper. The relationship between the academic research group and ESSA's commercial program is not fully clear from available disclosures. Worth noting that the pipeline from academic discovery to commercial development has not yet cleared a Phase 2 success — the most recent data point was negative.