What is heat shock protein 90?

Heat shock protein 90 (Hsp90) is an often-mentioned molecular chaperone. Heat shock protein 90 (Hsp90) exerts an important role in the maturation and stability of client proteins. Oncogenic client proteins, which are the target molecules of many anticancer compounds, and encompass dysregulated, mutated, and fusion proteins, are particularly dependent on Hsp90 for maintaining their conformation. The prevention of Hsp90 biological function is well known to result in the degradation of multiple client proteins implicated in the generation and development of tumor and the concurrent suppression of multiple oncogenic signaling pathways, leading to signal transduction loss, growth inhibition, cell death, and anti-angiogenesis. Moreover, Hsp90 is present in an activated multi-chaperone complex in tumor cells, and increased expression of Hsp90 is related with poor prognosis in patients with breast cancer. Therefore, inhibition of targeting Hsp90 is considered to be a promising strategy for treating cancer.[1]

HER2 and Hsp inhibitors

The overexpression of human epidermal growth factor receptor 2 (HER2), a receptor tyrosine kinase which serves as an oncogene, is also related with poor prognosis in breast cancer, as well as gastric cancers. Definitely, HER2 and HER3 frequently form a heterodimer as an oncogenic unit which plays an important role in HER2-mediated signaling in HER2-overexpressing breast cancers. In spite of both trastuzumab, which is a humanized mAb directed against HER2, and lapatinib, which is an epidermal growth factor receptor (EGFR) and HER2 dual-kinase inhibitor, have demonstrated good initial clinical efficacy and are considered standard-of-care drugs, clinical relapse with trastuzumab or lapatinib therapy has been noticed in some patients. Therefore, more effective therapy of HER2-overexpressing tumors is required, and forming rationalized combinations of agents appears particularly promising. As HER2 is a representative client protein which depends on the biological functions of Hsp90 for stability, the Hsp90 inhibitor is effective against HER2-overexpressing tumors. However, first-generation geldanamycin derivatives have been proved to pose a risk of hepatotoxicity and efflux by P-glycoprotein, and have not yet been approved for cancer therapy. To resolve these drawbacks, a series of second-generation Hsp90 inhibitors have been designed, synthesized and are currently in clinical development.

How is the pharmacological of CH5164840?

Recently, CH5164840 as a novel Hsp90 inhibitor with a unique chemical structure through virtual screening based on a 3-D structure was validated. Its induction of oncogenic client protein degradation, antiproliferative activity, and apoptosis against an NCI-N87 gastric cancer cell line and a BT-474 breast cancer cell line was investigated. Intriguingly, CH5164840 indicated tumor selectivity both in vitro and in vivo, binding to tumor Hsp90 (which forms active multiple chaperone complexes) in vitro, and being distributed effectively to tumors in a mouse model, which, taken together, supports the decreased levels of phosphorylated Akt by CH5164840 that we observed in tumor tissues, but not in normal tissues. As well as being well tolerated, the oral administration of CH5164840 displayed potent antitumor efficacy with regression in NCI-N87 and BT-474 tumor xenograft models. Additionally, CH5164840 significantly increased antitumor efficacy against gastric and breast cancer models when combined with the human epidermal growth factor receptor 2 (HER2)-targeted drugs, trastuzumab and lapatinib. These results demonstrate the potent antitumor efficacy of CH5164840 when administered alone, and its effective combination efficacy when combined with trastuzumab or lapatinib, supporting the clinical development of CH5164840 as an Hsp90 inhibitor for combination treatment with HER2-targeted agents against HER2-overexpressing tumors.

Sources: Cancer Res 2005; 65: 10686, Bioorg Med Chem Lett 2011; 21: 577.