In addition to the above uses of pyrazole as therapeutic agent, it has recently been recognized to have modulatory effect on UPR, especially for the treatment of cancers and other diseases. The benzyl pyrazole derivative HSF1A, a small molecule activator of HSF-1, was identified in a yeast-based high-throughput screen (72). Induction of chaperones by HSF1A was shown to reduce protein misfolding and aggregation-mediated toxicity in cellular and fly models of polyQ-related diseases, and to activate HSF-1 in Drosophila and mammalian cells without inhibition of Hsp90 activity or causing proteotoxicity. Rather, HSF1A was suggested to interact with the cytosolic TCP-1 ring complex (TRiC). This proposed mechanism of action is of interest as TRiC…show more content… CNB-001, pyrazole derivative of curcumin for its ability to reduce intracellular Aβ induces eIF2 and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2 phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβand ubiquitinated aggregated proteins (80). Pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole- 5-carboxamide (4f) inhibit Nrf2, which is persistently activated in many human tumors including AML. s. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2–associated X protein (Bax) ratio, which indicated that 4f induced apoptosis (81).
Ceapins, a class of pyrazole amides have ability to inhibit the processing of ATF6α by S1P and S2P in response to ER stress. It was demonstrated by probing each step of ATF6α activation that these ceapins prevent selection of ATF6α into COPII vesicles by retaining it in place in the ER membrane. In presence of ceapins,it was shown that ATF6α restores the cleavage by removing the requirement for trafficking that involves bringing together substrate and proteases. Rapid clustering of ATF6α has been shown to be induced by Ceapins that depicts that the oligomeric state of ATF6α has to play a key role