PROSTATE CANCER

UT-34: a promising new AR degrader

UT-34, a newly discovered second-generation selective agent for the degradation of androgen receptor (SARD), degrades enzalutamide-sensitive and enzalutamide-resistant androgen receptors (ARs) and AR splice variants (ARVs) in preclinical models of prostate cancer. This orally bioavailable SARD has promising drug-like characteristics and should progress to clinical development.

UT-34 was selected for further characterization from a library owing to its favourable degradation and antagonistic characteristics and pharmacokinetic properties compared with first-generation SARDs, whose pharmacokinetic properties were inappropriate for further development.

In vitro, UT-34 antagonized wild-type AR with a similar half-maximal inhibitory concentration (IC50) to enzalutamide and had similar or better IC50s in AR mutants. In LNCaP cells, UT-34 reduced AR protein levels, unlike enzalutamide or bicalutamide, and also downregulated AR in enzalutamide-resistant MR49F cells. In cross-reactivity experiments, UT-34 did not degrade other receptors.

Further analyses suggested that, to degrade AR, UT-34 requires the ubiquitin proteasome pathway. Moreover, UT-34 was found to bind to the activation function 1 region of AR. In LNCaP and LNCaP95 cells, treatment with UT-34 downregulated AR and AR-V7. Drug metabolism and pharmacokinetic assays showed that UT-34 is stable and efficacious.

In vivo, oral treatment with UT-34 shrank the prostate more than treatment with enzalutamide. UT-34 treatment also decreased the growth of the enzalutamide-resistant, castration-resistant xenografts.

These data show that UT-34 is a promising SARD for the treatment of enzalutamide-resistant prostate cancer and warrants further clinical development.

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  1. Ponnusamy, S. et al. Orally-bioavailable androgen receptor degrader, potential next-generation therapeutic for enzalutamide-resistant prostate cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-1458 (2019)

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Correspondence to Louise Stone.

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Stone, L. UT-34: a promising new AR degrader. Nat Rev Urol 16, 640 (2019). https://doi.org/10.1038/s41585-019-0248-5

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