AUTHOR=Go Young-Hyun , Lim Changjin , Jeong Ho-Chang , Kwon Ok-Seon , Chung Sungkyun , Lee Haeseung , Kim Wankyu , Suh Young-Ger , Son Woo Sung , Lee Mi-Ok , Cha Hyuk-Jin , Kim Seok-Ho TITLE=Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells JOURNAL=Frontiers in Chemistry VOLUME=7 YEAR=2019 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00298 DOI=10.3389/fchem.2019.00298 ISSN=2296-2646 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.