Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor

Yan Xiong, Holger Greschik, Catrine Johansson, Ludwig Seifert, Vicki Gamble, Kwang Su Park, Vincent Fagan, Fengling Li, Irene Chau, Masoud Vedadi, Cheryl H. Arrowsmith, Paul Brennan, Oleg Fedorov, Manfred Jung, Gillian Farnie, Jing Liu, Udo Oppermann, Roland Schüle, Jian Jin

Research output: Contribution to journalArticlepeer-review

Abstract

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.

Original languageEnglish
Pages (from-to)5837-5853
Number of pages17
JournalJournal of Medicinal Chemistry
Volume67
Issue number7
DOIs
StatePublished - 11 Apr 2024

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