Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Proteostasis networks, including molecular chaperones HSP90 and HSP70 and the HSF1 stress pathway, are crucial in cancer cell survival.
• Dysregulation of these networks presents therapeutic opportunities in various cancers.

Purpose of the Study:

• To review the discovery and development of small-molecule inhibitors targeting HSP90, HSP70, and HSF1 for cancer therapy.
• To discuss progress, challenges, and future directions in targeting these proteostasis regulators.

Main Methods:

• Development of potent and selective chemical probes and drug candidates.
• Exploration of small-molecule inhibitors through phenotypic screening and rational drug design.
• Analysis of clinical activity and potential combination strategies for HSP90 inhibitors.

Main Results:

• Highly potent HSP90 inhibitors have been valuable research tools and shown clinical activity in non-small cell lung cancer and HER2-positive breast cancer.
• Progress in developing HSP70 inhibitors has yielded useful chemical tool compounds.
• HSF1 pathway inhibitors, identified via phenotypic screening, including bisamides, have led to a clinical candidate for ovarian cancer and multiple myeloma.

Conclusions:

• HSP90 inhibitors are valuable in cancer research and therapy, with combination strategies being key for optimal use.
• Developing effective HSP70 inhibitors remains challenging but shows recent progress.
• The HSF1 pathway is a validated cancer target, with inhibitors progressing to clinical trials.