Discovery of new celastrol derivatives with antitumor activity in vitro and in vivo by blocking Hsp90-Cdc37-kinase cycle

Hsp90-Cdc37-kinase cycle plays a critical role in the development of cancers. And the phosphorylation of Cdc37 (Serine13) by CK2 is a prerequisite. Celastrol (CEL) can interfere with Hsp90-Cdc37-kinase cycle by inhibiting Hsp90-Cdc37 protein-protein interaction (PPI) to exhibit antitumor effect. In this study, the pharmacophore of CK2 inhibitors was first introduced to CEL to obtain 18 derivatives to improve the antitumor activity, and the anti-proliferation of the derivatives was evaluated. Among them, compound 11 exhibited the most potent activity against MDA-MB-231 (IC₅₀ = 0.25 ± 0.02 μM) which was about 7 times that of CEL. Furthermore, 11 not only selectively inhibited CK2 activity, but also disrupted Hsp90-Cdc37 PPI, thereby leading to a sharp decrease on the level of kinase clients to arrest cell cycle and induce apoptosis. Moreover, 11 showed much higher tumor inhibition rate (65.3 %) than CEL (38.0 %) in vivo without obvious toxicity. Taken together, compound 11 could more effectively block Hsp90-Cdc37-kinase cycle, which might be a promising antitumor candidate.