Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors.

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Abiraterone acetate (AA) is an orally active CYP17A1 inhibitor used for prostate cancer treatment.
• AA inhibits both 17α-hydroxylase and 17,20-lyase activities of CYP17, leading to potential side effects like mineralocorticoid excess syndrome (MES).

Purpose of the Study:

• To design and develop novel, CYP17 lyase-selective inhibitors with improved safety and efficacy compared to abiraterone acetate.
• To explore new chemical methodologies for creating potent metalloenzyme inhibitors.

Main Methods:

• Rationally designed novel metal-binding groups, replacing high-affinity pyridine or imidazole moieties.
• Incorporated potency-enhancing molecular scaffold modifications.
• Developed a series of CYP17 lyase-selective inhibitors, including oral agent 6 (VT-464).

Main Results:

• Successfully designed and synthesized novel CYP17 lyase-selective inhibitors.
• Identified oral agent 6 (VT-464) as a promising candidate, currently in Phase 2 clinical trials for prostate cancer.
• Demonstrated the potential applicability of the chemical methodology to other metalloenzyme inhibitor designs.

Conclusions:

• The developed CYP17 lyase-selective inhibitors represent a potentially safer and more effective therapeutic strategy for prostate cancer.
• The chemical methodology employed is adaptable for designing novel treatments for various diseases targeting metalloenzymes.