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Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity
Darong Kim1, So-Yeon Kim2, Dongyoung Kim2
1New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea.
Abstract:
TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.
Insights
New pyrazolo[3,4-d]pyrimidine derivatives target TRAP1, a protein linked to cancer growth. These compounds show potent anticancer effects in cell and animal models with low toxicity, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial Hsp90 paralog implicated in cancer progression.
- TRAP1 influences tumorigenesis by maintaining mitochondrial integrity, regulating reactive oxygen species, and altering cellular metabolism.
- TRAP1 and Hsp90 are validated therapeutic targets in oncology.
Purpose of the Study:
- To design and synthesize novel mitochondria-permeable pyrazolo[3,4-d]pyrimidine derivatives as TRAP1 inhibitors.
- To optimize lead compounds for enhanced potency, metabolic stability, and safety profiles.
- To evaluate the anticancer efficacy of identified inhibitors in preclinical cancer models.
Main Methods:
- Structure-based drug design was employed for lead optimization.
- In vitro assays assessed TRAP1 and Hsp90 inhibition, metabolic stability, and CYP/hERG activity.
- X-ray co-crystallization confirmed target engagement within the ATP binding pocket.
- Anticancer activity was evaluated in various cancer cell lines and in mouse xenograft models.
Main Results:
- Novel pyrazolo[3,4-d]pyrimidine derivatives were identified as potent TRAP1 inhibitors.
- Compounds 47 and 48 exhibited strong TRAP1 and Hsp90 inhibition with favorable pharmacokinetic properties.
- X-ray crystallography validated the binding mode of compounds 47 and 48 in the TRAP1 ATP pocket.
- Compounds 47 and 48 demonstrated significant anticancer efficacy in vitro and reduced tumor growth in vivo with minimal toxicity to normal cells.
Conclusions:
- Mitochondria-permeable pyrazolo[3,4-d]pyrimidine derivatives are effective TRAP1 inhibitors.
- Compounds 47 and 48 represent promising lead candidates for cancer therapy targeting TRAP1.
- These findings support the therapeutic potential of targeting TRAP1 in various cancers.
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