Xiong, Yan and Greschik, Holger and Johansson, Catrine and Seifert, Ludwig and Bacher, Jahannes and Park, Kwang-su and Babault, Nicolas and Martini, Michael and Fagan, Vincent and Li, Fengling and Chau, Irene and Christott, Thomas and Dilworth, David and Barsyte-Lovejoy, Dalia and Vedadi, Masoud and Arrowsmith, Cheryl H. and Brennan, Paul and Fedorov, Oleg and Jung, Manfred Jung and Farnie, Gillian and Lui, Jing and Oppermann, Udo and Schüle, Roland and Jin, Jian (2019) Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1). Journal of Medicinal Chemistry, 62 (20). pp. 8996-9007. ISSN 0022-2623

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Abstract

By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.

Item Type:	Article
Additional Information:	R.S. acknowledges support by grants of the European Research Council (ERC AdGrant 322844) and the Deutsche Forschungsgemeinschaft CRC 992, 850, and Schu688/15-1. M.J. thanks the DFG (Deutsche Forschungsgemeinschaft, CRC992) for funding. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Well- ̃ come [106169/ZZ14/Z]. We acknowledge the Natural Sciences and Engineering Research Council of Canada (NSERC) for a postdoctoral fellowship awarded to D.D. We thank Drs. Benchimol and McPherson for providing 293T and C2C12 cells. Cite as: J. Med. Chem. 2019, 62, 20, 8996–9007 Publication Date:July 1, 2019 https://doi-org.jproxy.nuim.ie/10.1021/acs.jmedchem.9b00522
Keywords:	Potent and Selective Fragment-like Inhibitor; Methyllysine Reader Protein Spindlin 1 (SPIN1);
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	15039
Identification Number:	https://doi.org/10.1021/acs.jmedchem.9b00522
Depositing User:	Vincent Fagan
Date Deposited:	30 Nov 2021 15:37
Journal or Publication Title:	Journal of Medicinal Chemistry
Publisher:	ACS Publications
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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