Small Molecule Inhibitors Targeting Heat Shock Response Pathways: Lessons from Clinical and Preclinical Studies in Cance
Introduction Heat shock response (HSR) pathway is a highly conserved cellular process. HSF1 is a master transcriptional regulator responsible for the expression of several important heat shock proteins (HSP), which can effectively protect critical client
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Abstract Introduction Heat shock response (HSR) pathway is a highly conserved cellular process. HSF1 is a master transcriptional regulator responsible for the expression of several important heat shock proteins (HSP), which can effectively protect critical client proteins from misfolding and degradation, thus maintaining intracellular integrity under stressed conditions. Recent studies have demonstrated the direct connections between HSR players and tumor cell survival, validating HSR players as novel molecular targets in anticancer treatment. Small molecule screening has produced some promising HSR inhibitors for anticancer treatment. In this article, we aim to summarize the main findings from HSR inhibitors on recent clinical and preclinical studies. Methods The authors reviewed all the relevant papers of HSR inhibitors with an emphasis on human and animal studies. Results More than 18 unique chemical identities have been discovered with confirmed inhibition of HSR pathway. Among them, two natural products and their derivatives are currently in various phases of clinical studies. Detailed works are required to define the exact mechanisms of actions (MOA) for these compounds. Conclusion Many hurdles in clinical application still need to be effectively addressed, such as undesirable drug toxicity and off-target effects; narrow therapeutic window; poor PK/PD profiles, etc. Recent reports on synergistic drug combination, advanced prodrug design, smart nanoparticle packaging, and RNA aptamer selection offer promising solutions to overcome these challenges. Future advancements in this fast-growing area can potentially lead to the next-generation cancer therapeutics.
D. Zhang · D. Wang · B. Zhang (*) Alpine Therapeutics Inc., San Diego, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. A. Asea, P. Kaur (eds.), Heat Shock Proteins, https://doi.org/10.1007/7515_2020_2
D. Zhang et al.
Keywords Cancer · Clinical trial · Drug discovery · HSF1 · HSP · HSR, inhibitor · Mouse xenograft · Small molecule
Abbreviations HCS HSE HSF1 HSP HSR HTS MOA NCT PD PK SAR target ID
high content screening heat shock element heat shock factor 1 heat shock protein heat shock response high throughput screening mechanism of action ClinicalTrials.gov identifier number pharmacodynamics pharmacokinetics structure-activity relationship target identification
1 Introduction Cancer is a malignant disease characterized by uncontrolled cell growth. Genetic and epigenetic alterations can activate oncogenes whose activities are necessary for tumor initiation and maintenance, a phenomenon called “oncogene addiction.” [75]. As a result of this oncogenic transformation, cancer cells are known to exhibit “stress phenotype”, such as high levels of DNA damage, aneuploidy, and reactive oxygen species [21]. These cancer cells constantly express mutated oncogenes with misfolded protein structures. Comparing to their normal counterparts, the transformed malignant cells demand a much higher expression level of molecular chaperone proteins,
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