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Published on: September 30, 2019
Privileged Scaffolds in Drug Discovery against Human Epidermal Growth Factor Receptor 2 for Cancer Treatment
Mudasir Nabi Peerzada1, Rania Hamdy2,3, Masood Ahmad Rizvi4
1Tumor Biology and Drug Discovery Laboratory, National Institute of Pathology, Indian Council of Medical Research, Safdarjang Hospital Campus, New Delhi 110029, India.
Abstract:
HER2 is the membrane receptor tyrosine kinase showing overexpression in several human malignancies, particularly breast cancer. HER2 overexpression causes the activation of Ras- MAPK and PI3K/Akt/ NF-κB cellular signal transduction pathways that lead to cancer development and progression. HER2 is, therefore, presumed as one of the key targets for the development of tumor-specific therapies. Several preclinical have been developed that function by inhibiting the HER2 tyrosine kinase activity through the prevention of the dimerization process. Most HER2 inhibitors act as ATP competitors and prevent the process of phosphorylation, and abort the cell cycle progression and proliferation. In this review, the clinical drug candidates and potent pre-clinical newly developed molecules are described, and the core chemical scaffolds typically responsible for anti-HER2 activity are deciphered. In addition, the monoclonal antibodies that are either used in monotherapy or in combination therapy against HER2-positive cancer are briefly described. The identified key moieties in this study could result in the discovery of more effective HER2-targeted anticancer drug molecules and circumvent the development of resistance by HER2-specific chemotherapeutics in the future.
Insights
This review details HER2 inhibitors for cancer therapy, focusing on small molecules and monoclonal antibodies that block HER2 signaling pathways. These targeted therapies aim to improve treatment efficacy and overcome drug resistance in HER2-positive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2 (Human Epidermal growth factor Receptor 2) is a receptor tyrosine kinase overexpressed in various cancers, notably breast cancer.
- HER2 overexpression activates critical signaling pathways like Ras-MAPK and PI3K/Akt/NF-κB, driving tumor development and progression.
- HER2 is a validated target for developing targeted anticancer therapies.
Approach:
- This review synthesizes information on preclinical and clinical drug candidates targeting HER2.
- It analyzes core chemical scaffolds responsible for anti-HER2 activity in small molecule inhibitors.
- Monoclonal antibodies used in monotherapy or combination therapy for HER2-positive cancers are also discussed.
Key Points:
- HER2 inhibitors function by blocking tyrosine kinase activity, often by competing with ATP and preventing phosphorylation.
- Inhibitors disrupt cell cycle progression and proliferation in HER2-overexpressing cancer cells.
- Understanding key chemical moieties and antibody strategies is crucial for developing next-generation HER2-targeted drugs.
Conclusions:
- The identified chemical scaffolds and therapeutic strategies offer potential for discovering more effective HER2-targeted anticancer agents.
- This research may help circumvent resistance mechanisms developed against current HER2-specific chemotherapeutics.
- Further development of these targeted therapies holds promise for improved outcomes in HER2-positive malignancies.
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