Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers
Yusuke Oku,
Naoyuki Nishiya,
Toshiya Shito,
Reiichiro Yamamoto,
Yasufumi Yamamoto,
Chihiro Oyama,
Yoshimasa Uehara
Affiliations
Yusuke Oku
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Naoyuki Nishiya
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Toshiya Shito
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Reiichiro Yamamoto
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Yasufumi Yamamoto
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Chihiro Oyama
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Yoshimasa Uehara
Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
YAP and TAZ oncoproteins confer malignancy and drug resistance to various cancer types. We screened for small molecules that inhibit the nuclear localization of YAP/TAZ. Dasatinib, statins and pazopanib inhibited the nuclear localization and target gene expression of YAP and TAZ. All three drugs induced phosphorylation of YAP and TAZ, and pazopanib induced proteasomal degradation of YAP/TAZ. The sensitivities to these drugs are correlated with dependence on YAP/TAZ in breast cancer cell lines. Combinations of these compounds with each other or with other anti‐cancer drugs efficiently reduced cell proliferation of YAP/TAZ‐dependent breast cancer cells. These results suggest that these drugs can be therapeutics and chemosensitizers for YAP/TAZ‐dependent breast cancers.
