Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective
This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer—specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. E
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Paul Workman
Abstract
This personal perspective focuses on small- molecule inhibitors of proteostasis networks in cancer—specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of P. Workman (*) CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK e-mail: [email protected]
bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers. Keywords
HSP90 · HSP70 · HSF1 · Chemical probes · Drug discovery · Biomarkers · Translational research
11.1 Introduction It seems very fitting that a collection of articles on proteostasis networks in cancer – and one that is dedicated to the extraordinary life and work of Sue Lindquist – should conclude with a piece on experience with preclinical and clinical translation in this area. I feel privileged to be invited to provide a short article on my reflections on progress made, lessons learned and an outlook for the future in this field. This brief commentary is written very much as a personal perspective – based on more than two decades of involvement working on chemical biology and drug discovery around HSP90, HSP70 and HSF1 as molecular targets. I will mainly illustrate the progress and challenges based on the work carried out in my own laboratory – in association with many talented colleagues and collaborators. I will also
© Springer Nature Switzerland AG 2020 M. L. Mendillo et al. (eds.), HSF1 and Molecular Chaperones in Biology and Cancer, Advances in Experimental Medicine and Biology 1243, https://doi.org/10.1007/978-3-030-40204-4_11
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refer to the work of others, but I apologise to the many excellent scientists in the field that it is in the nature of a short personal perspective that exhaustive referencing is not possible. Sue Lindquist was an outstanding scientist and true pioneer in the field of proteostasis. Her curiosity and great aptitude for the basic science coupled with a strong desire to make a difference to human disease led her to wor
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