title: Preclinical antitumor activity of the novel heat shock protein 90 inhibitor CH5164840 against human epidermal growth factor receptor 2 (HER2)-overexpressing cancers.
abstract: 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.
authors: Pharmaceutical Research Department 2, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan. ononom@chugai-pharm.co.jp
authors: Naomi
authors: N
authors: Ono
authors: Toshikazu
authors: T
authors: Yamazaki
authors: Yoshito
authors: Y
authors: Nakanishi
authors: Toshihiko
authors: T
authors: Fujii
authors: Kiyoaki
authors: K
authors: Sakata
authors: Yukako
authors: Y
authors: Tachibana
authors: Atsushi
authors: A
authors: Suda
authors: Kihito
authors: K
authors: Hada
authors: Takaaki
authors: T
authors: Miura
authors: Shigeo
authors: S
authors: Sato
authors: Ryoichi
authors: R
authors: Saitoh
authors: Kohnosuke
authors: K
authors: Nakano
authors: Takuo
authors: T
authors: Tsukuda
authors: Toshiyuki
authors: T
authors: Mio
authors: Nobuya
authors: N
authors: Ishii
authors: Osamu
authors: O
authors: Kondoh
authors: Yuko
authors: Y
authors: Aoki
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000096:biosynthesis; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000077341:Lapatinib; D051058:Oncogene Protein v-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C570831:CH5164840; C508053:ERBB2 protein, human