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      Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells

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          Abstract

          Despite great potential for regenerative medicine, the high tumorigenic potential of human pluripotent stem cells (hPSCs) to form undesirable teratoma is an important technical hurdle preventing safe cell therapy. Various small molecules that induce the complete elimination of undifferentiated hPSCs, referred to as “stemotoxics,” have been developed to facilitate tumor-free cell therapy, including the Survivin inhibitor YM155. In the present work, based on the chemical structure of YM155, total 26 analogs were synthesized and tested for stemotoxic activity toward human embryonic stem cells (hESCs) and induced PSCs (iPSCs). We found that a hydrogen bond acceptor in the pyrazine ring of YM155 derivatives is critical for stemotoxic activity, which is completely lost in hESCs lacking SLC35F2, which encodes a solute carrier protein. These results suggest that hydrogen bonding interactions between the nitrogens of the pyrazine ring and the SLC35F2 protein are critical for entry of YM155 into hPSCs, and hence stemotoxic activity.

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          Most cited references 32

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          Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

          The Lancet, 385(9967), 509-516
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            YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.

            Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.
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              The tumorigenicity of human embryonic stem cells.

              Human embryonic stem cells (HESCs) are the in vitro descendants of the pluripotent inner cell mass (ICM) of human blastocyst stage embryos. HESCs can be kept undifferentiated in culture or be differentiated to tissues representing all three germ layers, both in vivo and in vitro. These properties make HESC-based therapy remarkably appealing for the treatment of various disorders. Upon transplantation in vivo, undifferentiated HESCs rapidly generate the formation of large tumors called teratomas. These are benign masses of haphazardly differentiated tissues. Teratomas also appear spontaneously in humans and in mice. When they also encompass a core of malignant undifferentiated cells, these tumors are defined as teratocarcinomas. These malignant undifferentiated cells are termed embryonic carcinoma (EC), and are the malignant counterparts of embryonic stem cells. Here we review the history of experimental teratomas and teratocarcinomas, from spontaneous teratocarcinomas in mice to induced teratomas by HESC transplantation. We then discuss cellular and molecular aspects of the tumorigenicity of HESCs. We also describe the utilization of HESC-induced teratomas for the modeling of early human embryogenesis and for modeling developmental diseases. The problem of HESC-induced teratomas may also impede or prevent future HESC-based therapies. We thus conclude with a survey of approaches to evade HESC-induced tumor formation.
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                Author and article information

                Contributors
                Journal
                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                2296-2646
                16 May 2019
                2019
                : 7
                Affiliations
                1Department of Life Sciences, College of Natural Sciences, Sogang University , Seoul, South Korea
                2Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University , Pochen-si, South Korea
                3Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon, South Korea
                4Department of Life Science, Ewha Womans University , Seoul, South Korea
                5College of Pharmacy, Seoul National University , Seoul, South Korea
                6Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul, South Korea
                Author notes

                Edited by: Simone Brogi, University of Pisa, Italy

                Reviewed by: Keiichi Fukuda, School of Medicine, Keio University, Japan; In-Hyun Park, Yale University, United States; Andrew Laslett, Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Australia

                *Correspondence: Mi-Ok Lee molee@ 123456kribb.re.kr

                This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry

                †These authors have contributed equally to this work

                Article
                10.3389/fchem.2019.00298
                6532689
                Copyright © 2019 Go, Lim, Jeong, Kwon, Chung, Lee, Kim, Suh, Son, Lee, Cha and Kim.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 38, Pages: 16, Words: 9266
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: NRF-2017M3A9B3061843
                Award ID: NRF-2017R1D1A1B03034612
                Funded by: Seoul National University 10.13039/501100002551
                Award ID: 370C-20180086
                Categories
                Chemistry
                Original Research

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