BBA Advances 1 (2021) 100008 Contents lists available at ScienceDirect BBA Advances journal homepage: www.elsevier.com/locate/bbadva Narciclasine is a novel YAP inhibitor that disturbs interaction between YAP and TEAD4 Rie Kawamoto a,# , Naoko Nakano a,# , Haruka Ishikawa a,# , Etsu Tashiro a , Waka Nagano a , Keigo Sano a , Miki Irie a , Mariko Ikuta a , Fukuko Kishi a , Takahisa Nakane b , Mikihiko Naito c , Susumu Itoh 1,∗ a Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan b Laboratory of Natural Products Chemistry, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan c Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan a r t i c l e i n f o Keywords: Anticancer drug Malignant mesothelioma Narciclasine TEAD YAP a b s t r a c t Yes-associated protein (YAP) is involved in development, cell growth, cell size, and homeostasis and plays a key role in the progression of various cancers. Among them, constitutive activation of YAP can often be observed in malignant mesothelioma, which arises in the pleura, peritoneum, and pericardium because of inactivation of the Hippo pathway. To date, however, only less-effective treatments such as chemotherapy, radiation therapy, and surgery are available for patients with malignant mesothelioma. In this study, we identified narciclasine as a novel YAP inhibitor that prevents YAP from interacting with TEAD4 because it competes with TEAD4 for binding to YAP. Furthermore, narciclasine could perturb the cell growth and colony formation of malignant mesothelioma NCI-H290 cells in addition to inhibiting their growth in nude mice. Therefore, narciclasine might be a potential seed for a novel antitumor drug against malignant mesothelioma and other cancers in which hyperactivation and/or overexpression of YAP are observed. 1. Introduction Malignant mesothelioma arises from mesothelial cells lining the serous membranes of the pleura, peritoneum, pericardium, and tunica vaginalis [1]. After exposure to asbestos, an incubation period of over 30 years is required for mesothelial cells in the human body to be trans- formed into mesothelioma [2]. When patients are diagnosed with ma- lignant mesothelioma, the tumors cannot be completely excised through surgery and/or radiation therapy because malignant mesothelioma is a disseminated cancer. Therefore, patients with malignant mesothelioma have waited for revolutionary anti-mesothelioma drugs. Yes-associated protein (YAP) is a key attributor to cancer cells be- cause high levels and/or aberrant activation of YAP constitutively pro- mote cell proliferation. In addition, YAP potentiates the ability of cancer stem cells (CSCs), including their expansion, drug resistance, and plas- ticity [3]. It is well known that YAP is involved in the development of distinct tumor types in humans and mice [3-5]. Thus, as an oncogene, ∗ Corresponding author at: Susumu Itoh, Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194- 8543, Japan. E-mail address: sitoh@ac.shoyaku.ac.jp (S. Itoh). # Contributed equally. YAP seems to be essential for tumor initiation, progression, and metas- tasis. The activity of YAP is tightly regulated by the Hippo pathway, which is implicated in tissue growth, cell proliferation, differentiation, and mi- gration in developing organs. Mechanistical stimulation such as cell-cell contact and cell polarity triggers activation of TAO kinases, followed by phosphorylation of MSTs (mammalian Ste20-like kinases). Then, MSTs catalyze the phosphorylation of Lats1/2 (large tumor suppressor 1/2). Phosphorylated Lats1/2 can facilitate their autophosphorylation to be- come active kinases. Subsequently, YAP and/or its homolog, TAZ (tran- scriptional coactivator with PDZ-binding motif) (Fig. 1A), are phospho- rylated by Lats1/2 to become inactive forms. NF2 is well known as an- other important player that activates Hippo signaling. NF2 can directly interact with Lats1/2 or indirectly associate with them via MSTs. When the Hippo signal is therefore not transduced, YAP and/or TAZ can be localized to the nucleus, where YAP and/or TAZ bind to the TEAD (TEA domain) family (ie, TEAD1–4) to promote cell growth, survival, migra- tion, and so forth [6]. On the other hand, phosphorylated YAP and/or TAZ are degraded via the proteasome pathway or retained in the cytosol by their interaction with 14-3-3. Consequently, interference of YAP- or https://doi.org/10.1016/j.bbadva.2021.100008 Received 5 December 2020; Received in revised form 5 March 2021; Accepted 17 March 2021 Available online 27 March 2021 2667-1603/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)