Discovery of Novel Celastrol Derivatives as Hsp90–Cdc37 Interaction Disruptors with Antitumor Activity

Abstract

To develop novel and efficient heat shock protein 90–cell division cycle 37 (Hsp90–Cdc37) interaction disruptors, several lipophilic fragments were introduced into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all the target compounds, 41 was screened with superior antiproliferative activity on related cancer cells (IC50: 0.41–0.94 μM) and 41 could decrease the level of the Hsp90–Cdc37 complex in A549 cells. The capability to disrupt the Hsp90–Cdc37 interaction was stronger than that of CEL. Furthermore, pull-down assay, UV assay, and molecular docking analysis all showed that 41 might disrupt the interaction of the Hsp90–Cdc37 complex by preferentially binding to Cdc37 in cancer cells. Further studies showed that 41 could significantly regulate the levels of Hsp90–Cdc37 clients, thereby inducing the apoptosis of cancer cells. Together, 41 is a novel Hsp90–Cdc37 disruptor by binding to Cdc37 (hydrogen bond and/or covalent bond). Our results may provide reference for the discovery of effective Hsp90–Cdc37 disruptors.

Chemoproteomic profiling reveals celastrol as a potential modulator of cholesterol signaling

“…9 A recent study further showed that modification on this site with lipophilic fragments even increased its anti-proliferative activity by disrupting Hsp90–Cdc37 complex. 14 Luckily, the probe fully retained both HSR-inducing and Hsp90's client protein degradation activities, as evidenced by the increased expression of the HSR marker Hsp70 and downregulating of Raf-1 and Cdk4, two known clients of Hsp90, respectively (Fig. S1D, ESI†).…”

“…4B and Table S3, ESI†). Other known celastrol-related pathways such as chaperone, 4,14 glycolysis, 18 and lipid metabolism, 19 were included in the top 10 categories (Tables S4 to S6, ESI†). Further analysis with KEGG disease database revealed these targets were associated with numerous diseases, among which the term “plasma HDL-cholesterol (HDLC) levels” represents one of the top ones (Fig.…”

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

“…To improve the drug-like properties of celastrol, many celastrol derivatives have recently been produced. Two of them (9 and 10) have been selected for improved Hsp90-Cdc37 disruption activity and antiproliferative activity [73,74]. Although celastrol has non-negligible anti-tumor efficacy [75], it possesses an extensive medical value in the treatment of neurodegenerative diseases such as AD, PD, ALS, cerebral ischemia, multiple sclerosis, and spinal cord injury, which has been well-summarized in a recently published review [76].…”

Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

“…According to the SAR analysis of these substances, the conversion of the C‐20 carboxylic acid into polar groups improved the Hsp90‐Cdc37 disruption activity. Recently, Li et al 85 synthesized 48 celastrol derivatives via linking cinnamic acid or its analogues to the C‐20 carboxylic acid of celastrol (Scheme 9). Among them, Compound 93 showed a greater inhibition of the Hsp90−Cdc37 interaction.…”