Hsp90-Targeted Library
ChemDiv’s library of the HSP90-Targeting inhibitors contains 10,991 compounds.
Heat Shock Protein 90 (HSP90) is a key component in cancer development and other diseases due to its function as a molecular chaperone that contributes to the proper folding, stability, and function of many client proteins, including several oncogenes and signaling molecules. In cancer, HSP90 is often overexpressed and assists in maintaining the functional conformation of numerous mutated and overactive oncoproteins, thereby contributing to cancer cell survival, growth, and resistance to therapies. Inhibiting HSP90 disrupts these processes, leading to the degradation of its client proteins and, consequently, the suppression of tumor growth and metastasis. Beyond cancer, HSP90 is involved in neurodegenerative diseases like Alzheimer's and Parkinson's, where its role in protein folding is crucial for preventing the aggregation of misfolded proteins. Additionally, HSP90 is implicated in infectious diseases, as it assists in the folding of viral proteins necessary for pathogen survival. Therefore, targeting HSP90 has become a strategy in developing therapies for cancer, neurodegenerative disorders, and certain infectious diseases, offering potential therapeutic benefits by impacting multiple key proteins simultaneously.
HSP90 is a valuable target in drug discovery, particularly for cancer therapeutics, By inhibiting HSP90, these client proteins, including various kinases, hormone receptors, and transcription factors, become destabilized and are targeted for degradation, thereby disrupting multiple signaling pathways critical for cancer cell survival and proliferation. This multi-targeted approach can overcome the limitations of therapies that target individual oncogenic proteins, potentially reducing the likelihood of resistance development. Furthermore, HSP90 inhibitors have been shown to be beneficial for the treatment of neurodegenerative diseases by preventing the misfolding and aggregation of proteins implicated in these conditions. The broad spectrum of client proteins associated with HSP90 makes it a potential target for the pharmacotherapy of infectious diseases, as it is involved in viral protein folding, which is essential for the replication and survival of pathogens. Thus, HSP90 serves as a critical focal point in drug discovery efforts, offering a unique approach to simultaneously disrupt multiple disease pathways, particularly in complex diseases like cancer and neurodegenerative disorders.
The application of HSP90 inhibitors has led to notable successes, especially in oncology. These inhibitors have been effective in treating a diverse array of cancers, including breast, lung, melanoma, and gastrointestinal tumors, by destabilizing multiple oncogenic proteins that HSP90 stabilizes. One of the key benefits of HSP90 inhibitors is their ability to overcome drug resistance, as they target a broad range of signaling pathways and client proteins in tumor cells. Additionally, they have shown therapeutic potential in enhancing the effectiveness of other cancer treatments when used in combination, providing synergistic effects. Beyond cancer, early research indicates potential benefits in treating neurodegenerative diseases like Alzheimer’s and Parkinson’s, as HSP90 plays a role in protein folding and may contribute to the pathological aggregation of proteins in these conditions.
Virtual screening strategy
The core screening strategy involves a detailed analysis of the structures of known HSP90 and HSP70 inhibitors, covering more than 1,000 molecules:
- Assessment of the HSP90 and HSP70 protein structures and the conformational changes within their active binding sites upon ligand binding,
- Identification and analysis of binding modes and allosteric binding sites,
- Incorporation of the selective HSP90 and HSP70 binders,
- Building, deployment, and validation of the 3D models of specific protein-ligand interactions.
- Selection of potential HSP90/70 active compounds from the ChemDiv library, counting over 1.6 million molecules and comprising various diverse structural determinants. These include similarity to known inhibitors, privileged scaffolds, and medicinal chemistry filters.
- Molecular docking of selected compounds, considering a 'Pro-Drug' approach.
The current collection of the HSP90 inhibitors offers a powerful tool for the antitumor drug discovery research ideas and following lead optimization process.