The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.
The
enhancer of zeste homologue 2 (EZH2) is the catalytic subunit
of polycomb repressive complex 2 that catalyzes methylation of histone
H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been
identified in hematologic malignancies and solid tumors. Based on
the structure of EPZ6438 (1) and the binding model with
PRC2, we designed a series of analogues aiming to improve the activities
of EZH2 mutants. Structure–activity relationship (SAR) exploration
at both enzymatic and cellular levels led to the discovery of inhibitor 29. In the biochemical assay, 29 inhibited EZH2
(IC50 = 26.1 nM) with high selectivity over other histone
methyltransferases. It was also potent against EZH2 mutants (EZH2
Y641F, IC50 = 72.3 nM). Furthermore, it showed no apparent
inhibitory activity against the human ether-á-go-go related
gene (hERG) (IC50 > 30 μM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration
and showed better efficacy than 1 in both Pfeiffer and
Karpas-422 cell-mediated xenograft mouse models, indicating that it
might be a new potential therapeutic candidate for EZH2 mutant cancers.
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