Scholars@Duke publication: Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365.

Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365.

Journal articles - Journal Article

Mortensen, DS; Nayak, S; Plantevin-Krenitsky, V; Horn, EJ; Meiring, J; Reiss, S; Peacock, K; Zhao, J; Ba, X; Norris, S; Alexander, M; Huang, D ...

Published in: J Med Chem

July 23, 2026

Published version (DOI) Link to item

Androgen receptor (AR) signaling is central to the progression of prostate cancer, including castration-resistant disease. Targeted protein degradation, particularly through heterobifunctional compounds, represents a significant advancement in eliminating disease-causing proteins beyond traditional inhibition. Here, we describe the medicinal chemistry discovery of BMS-986365, a novel dual-function AR degrader and an antagonist. BMS-986365 selectively and efficiently degrades both wild-type and clinically relevant mutant ARs while also antagonizing residual AR activity. This dual mechanism results in the robust inhibition of AR-driven pathways and prostate cancer cell growth. The development of BMS-986365 highlights the potential of targeted protein degradation strategies to overcome resistance and improve therapeutic outcomes in prostate cancer.

Duke Scholars

Author Donald Patrick McDonnell Pharmacology & Cancer Biology

Author John David Norris Pharmacology & Cancer Biology

Author Suzanne E Wardell Pharmacology & Cancer Biology

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Published In

J Med Chem

DOI

10.1021/acs.jmedchem.6c01590

EISSN

1520-4804

Publication Date

July 23, 2026

Volume

Issue

Start / End Page

16346 / 16362

Location

United States

Related Subject Headings

Structure-Activity Relationship
Receptors, Androgen
Proteolysis
Prostatic Neoplasms
Medicinal & Biomolecular Chemistry
Male
Ligands
Humans
Drug Discovery
Cell Proliferation

Citation

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Chicago

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MLA

NLM

Mortensen, D. S., Nayak, S., Plantevin-Krenitsky, V., Horn, E. J., Meiring, J., Reiss, S., … Xu, S. (2026). Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365. J Med Chem, 69(14), 16346–16362. https://doi.org/10.1021/acs.jmedchem.6c01590

Mortensen, Deborah S., Surendra Nayak, Veronique Plantevin-Krenitsky, Evan J. Horn, Joseph Meiring, Samantha Reiss, Kimberly Peacock, et al. “Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365.” J Med Chem 69, no. 14 (July 23, 2026): 16346–62. https://doi.org/10.1021/acs.jmedchem.6c01590.

Mortensen DS, Nayak S, Plantevin-Krenitsky V, Horn EJ, Meiring J, Reiss S, et al. Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365. J Med Chem. 2026 Jul 23;69(14):16346–62.

Mortensen, Deborah S., et al. “Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365.” J Med Chem, vol. 69, no. 14, July 2026, pp. 16346–62. Pubmed, doi:10.1021/acs.jmedchem.6c01590.

Mortensen DS, Nayak S, Plantevin-Krenitsky V, Horn EJ, Meiring J, Reiss S, Peacock K, Zhao J, Ba X, Norris S, Alexander M, Correa M, Huang D, Brazeau J-F, Sapienza J, Tehrani L, Nagy M, Whitefield B, Papa P, Harris R, Grant V, Norris JD, Ammirante M, Rychak E, Wardell SE, Tsuji T, Havens CG, Liu K, Piccotti JR, Dalvie D, Tang Y, Guerrero N, Sapinoso L, Baughman J, Cathers BE, Rolfe M, Hamann LG, McDonnell DP, Narla RK, Hansen JD, Xu S. Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365. J Med Chem. 2026 Jul 23;69(14):16346–16362.

Published In

J Med Chem

DOI

10.1021/acs.jmedchem.6c01590

EISSN

1520-4804

Publication Date

July 23, 2026

Volume

Issue

Start / End Page

16346 / 16362

Location

United States

Related Subject Headings

Structure-Activity Relationship
Receptors, Androgen
Proteolysis
Prostatic Neoplasms
Medicinal & Biomolecular Chemistry
Male
Ligands
Humans
Drug Discovery
Cell Proliferation