Heat shock protein 90 (Hsp90), a
molecular chaperone that plays a significant role in the stability and maturation of client
proteins, including oncogenic targets for cell transformation, proliferation, and survival, is an attractive target for
cancer therapy. We identified the novel Hsp90 inhibitor,
CH5164840, and investigated 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. Interestingly,
CH5164840 demonstrated
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 exhibited potent antitumor efficacy with regression in NCI-N87 and BT-474
tumor xenograft models. In addition,
CH5164840 significantly enhanced antitumor efficacy against gastric and
breast cancer models when combined with the
human epidermal growth factor receptor 2 (HER2)-targeted agents,
trastuzumab and
lapatinib. These data demonstrate the potent antitumor efficacy of
CH5164840 when administered alone, and its significant combination efficacy when combined with
trastuzumab or
lapatinib, supporting the clinical development of
CH5164840 as an Hsp90 inhibitor for combination
therapy with HER2-targeted agents against HER2-overexpressing
tumors.