Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer
Open accessAbstract
Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders.
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Short linkers can be used to modulate PROTAC molecular weights and properties.
“Short linkers can be used to modulate PROTAC molecular weights67 and properties65”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [65]
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- Authors
- Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., McEachern, D., Wang, Y., Metwally, H., Wang, L., Matvekas, A., Wen, B., Sun, D., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-08-25
- Volume
- 64
- Issue
- 17
- Pages
- 12831-12854
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC8880306
- OpenAlex
- W3195255962
- Cited by
- 170
- References
- 61
- Citations by year
- 2026: 21 · 2025: 37 · 2024: 51 · 2023: 31 · 2022: 30
- FWCI
- 9.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- University of Michigan Library
- Funders
- National Cancer Institute (P30CA046592, P50 CA186786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTAC degraders, androgen receptor, prostate cancer, oral bioavailability, thalidomide, small-molecule degraders, oral pharmacokinetics, tumor growth inhibition
- MeSH terms
- Administration, Oral, Animals, Antineoplastic Agents, Biological Availability, Half-Life, Humans, Injections, Intravenous, Male, Microsomes, Liver, Prostatic Neoplasms, Receptors, Androgen, Structure-Activity Relationship, Molecular Structure, Drug Delivery Systems, Area Under Curve, Xenograft Model Antitumor Assays, Mice, Drug Discovery, Androgen Receptor Antagonists
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