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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor
Srinivas R Kasibhatla1, Kevin Hong, Marco A Biamonte
1Department of Chemistry, Biogen Idec, Inc., 5200 Research Place, San Diego, CA 92122, USA. srinivasrao.kasibhatla@biogenidec.com
Abstract:
Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 microM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 microM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
Insights
Novel 2-amino-6-halopurine inhibitors target activated heat shock protein 90 (Hsp90) in cancer cells. These compounds show potent anti-cancer activity and tumor growth inhibition, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Heat shock protein 90 (Hsp90) is crucial for stabilizing oncogenic proteins.
- Malignant cells exhibit an activated form of Hsp90, distinct from the inactive form in normal tissues.
- Targeting Hsp90 offers a potential therapeutic strategy with a high index for cancer treatment.
Purpose of the Study:
- To develop novel, selective inhibitors of the activated form of Hsp90.
- To evaluate the efficacy of these inhibitors against cancer cell lines and in preclinical models.
Main Methods:
- Synthesis and characterization of a novel series of 2-amino-6-halopurine Hsp90 inhibitors.
- In vitro assays measuring Hsp90 inhibition (HER-2 degradation) and antiproliferative activity in tumor cell lines.
- In vivo studies assessing tumor growth inhibition in a mouse xenograft model.
Main Results:
- A lead compound, 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30), demonstrated high potency (IC50 = 0.009 microM in HER-2 assay, 0.03 microM in MCF7 cells).
- This new class of inhibitors exhibited greater affinity for the activated Hsp90 compared to previous series.
- Oral administration resulted in significant tumor growth inhibition (>80%) in N87 xenografts, comparable to 17-AAG.
Conclusions:
- Novel 2-amino-6-halopurine derivatives are potent Hsp90 inhibitors with selective affinity for the activated form.
- These compounds display significant antiproliferative and tumor growth inhibitory effects.
- This class of inhibitors represents a promising new avenue for cancer therapy.
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