In this study, we designed and synthesized a novel family of neolamellarin A derivatives that showed high inhibitory activity toward heat shock protein 90 (Hsp90), a kinase associated with cell proliferation. The 3,4-bis(catechol)pyrrole scaffold and the benzyl group with methoxy modification at N position of pyrrole are essential to the Hsp90 inhibitory activity and cytotoxicity of these compounds. Western blot analysis demonstrated that these compounds induced dramatic depletion of the examined client proteins of Hsp90, and accelerated cancer cell apoptosis. Docking simulations suggested that the binding mode of 9p was similar to that of the VER49009, a potent inhibitor of Hsp90. Further molecular dynamics simulation indicated that the hydrophobic interactions as well as the hydrogen bonds contributed to the high affinity of 9p to Hsp90.

01 Jan 2014·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC)

Q4 · MEDICINE

Article

Author: Park, Hee Baek ; Jung, Su Hyun ; Seo, Young Ho ; Jeong, Chul-Ho ; Jang, Won Jun

Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein.

01 Oct 2009·Molecular and Cellular BiochemistryQ3 · BIOLOGY

Inhibition of hepatic stellate cell proliferation by heat shock protein 90 inhibitors in vitro

Q3 · BIOLOGY

Article

Author: You-Hong Hu ; Xiao-Dong Zhang ; Gang Cheng ; He-Yao Wang ; Xu Sun

Hepatic stellate cells (HSCs) play an important role in the development of hepatic fibrosis. Heat shock protein 90 (Hsp90) is essential for the maturation and activity of a varied group of proteins involved in signal transduction and cell cycle regulation. In this study, we found that two Hsp90 inhibitors, VER-49009 and its analog VER-49009M, inhibited the proliferation of hepatic stellate cell line CFSC cells, and both of them induced G2 phase arrest in CFSC cells. Akt expression was decreased by the treatment of Hsp90 inhibitors in CFSC cells. Based on these findings, we propose that the inhibition of Hsp90 might be a rational approach in the prevention of liver fibrosis.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	GB	Cancer Research UK	06 Apr 2007

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