title: TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models.
abstract: The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo[3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90α and β that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90α and β alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. s-ohkubo@taiho.co.jp.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohkubo
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Muraoka
authors.affiliation: Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hitotsumachi
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Chihoko
authors.initials: C
authors.lastname: Yoshimura
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kitade
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kanoh
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yonekura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D010786:Photoreceptor Cells / Q000187:drug effects; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D012160:Retina / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; C533585:HSP90AA2P protein, human; C493165:HSP90AB1 protein, human; C000596495:pimitespib