Important Compound Classes
Title
Spirocyclic Androgen Receptor Protein Degraders
Patent Publication Number
WO 2021/055756 A1
Publication Date
March 25, 2021
Priority Application
62/902,714 and 63/024,697 US
Priority Date
September 29, 2019 and May 14, 2020
Inventors
Wang, S.; Han, X.; Xiang, W.; Miao, B.; Qin, C.; Zhao, L.; Lu, J.; Xu, T.; Yang, C.
Assignee Company
The Regents of the University of Michigan [US/US]; Office of Technology Transfer, 1600 Huron Parkway, second floor, Ann Arbor, MI 48109-2590.
Disease Area
Cancer
Biological Target
Androgen Receptor (AR)
Summary
Prostate cancer (PCa) is the most frequently diagnosed cancer among men in industrialized nations and remains a leading cause of cancer-related deaths despite improvements in medical treatments over the past three decades. Radiation therapy and surgery are used for localized malignancies in addition to androgen deprivation therapies (ADT) as front-line treatments for PCa patients with high-risk localized disease. Initial treatment for advanced tumors exploits the dependence of PCa cells on androgens, but many patients stop responding to treatment and develop castrate-resistant prostate cancer (CRPC). Androgen receptor (AR) is a transcription factor that dimerizes and translocates to the nucleus upon binding of androgens, where it induces expression of a variety of genes crucial for PCa cell survival and proliferation. The current predominant diagnosis of PCa is based on prostate-specific antigen (PSA) levels from blood samples. However, the PSA test is highly controversial as its often has false-positive when no cancer may be present or false-negative when the patient may have cancer, which creates anxiety and stress for patients and their families.
Previous successful strategies that target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition by AR antagonist such as enzalutamide and apalulamide (ARN-509). However, such agents become ineffective in advanced prostate cancer with AR gene mutation, amplification, and alternate splicing. Furthermore, in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon the AR signaling. As a result, AR still remains an attractive therapeutic target for mCRPC and the urgent need to develop new anti-AR therapies that inhibits or degrade ARs with alternative modes of action.
Proteolysis-targeting chimeras (PROTACs) have become a very hot topic in drug discovery and continue to receive tremendous attention as a new class of therapeutic agents. PROTAC consist of a warhead that binds a protein of interest (POI), a linker, and a ligand that recruits an E3 ubiquitin ligase. A functional PROTAC triggers the formation of a ternary complex POI-PROTAC-E3 ligase that results in the ubiquitination of the POI, followed by proteasomal degradation. Two oral PROTACs (ARV-110 and ARV-471) recently reached Phase 2 clinical trials, and the number of molecules investigated in this chemical space is expected to grow significantly in the next few years.
As a result of the key role AR plays in CRPC, AR degraders designed based upon the PROTAC strategy could be an effective approach for the treatment of CRPC when the disease becomes resistant to AR antagonists or to androgen synthesis inhibitors. This present Patent Highlight discloses heterobifunctional small molecules, which are androgen receptor (AR) degraders and are thus useful in treating diseases or conditions where degradation of the AR protein provides a therapeutic benefit to a subject.
Key Structures
Biological Assay
Western blotting methods. VCap xenograft model used in severe combined immunodeficient (SCID) mice and pharmacokinetic was done in mice and rats.
Biological Data
The Table below
show degradation (24 h treatment) in Vcap cells for exemplary compounds,
where A = > 90% degradation, B = > 50% degradation. Oral bioavailability
for compound 311 indicated 82 (%F).
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The author declares no competing financial interest.