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

doi:10.1021/acs.jmedchem.4c00121

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 journal › Article › peer-review

2 Scopus citations

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 language	English
Pages (from-to)	5837-5853
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.4c00121
State	Published - 11 Apr 2024

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Xiong, Y., Greschik, H., Johansson, C., Seifert, L., Gamble, V., Park, K. S., Fagan, V., Li, F., Chau, I., Vedadi, M., Arrowsmith, C. H., Brennan, P., Fedorov, O., Jung, M., Farnie, G., Liu, J., Oppermann, U., Schüle, R., & Jin, J. (2024). Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor. Journal of Medicinal Chemistry, 67(7), 5837-5853. https://doi.org/10.1021/acs.jmedchem.4c00121

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

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.",

author = "Yan Xiong and Holger Greschik and Catrine Johansson and Ludwig Seifert and Vicki Gamble and Park, {Kwang Su} and Vincent Fagan and Fengling Li and Irene Chau and Masoud Vedadi and Arrowsmith, {Cheryl H.} and Paul Brennan and Oleg Fedorov and Manfred Jung and Gillian Farnie and Jing Liu and Udo Oppermann and Roland Sch{\"u}le and Jian Jin",

note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society.",

year = "2024",

month = apr,

day = "11",

doi = "10.1021/acs.jmedchem.4c00121",

language = "English",

volume = "67",

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publisher = "American Chemical Society",

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Xiong, Y, Greschik, H, Johansson, C, Seifert, L, Gamble, V, Park, KS, Fagan, V, Li, F, Chau, I, Vedadi, M, Arrowsmith, CH, Brennan, P, Fedorov, O, Jung, M, Farnie, G, Liu, J, Oppermann, U, Schüle, R & Jin, J 2024, 'Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor', Journal of Medicinal Chemistry, vol. 67, no. 7, pp. 5837-5853. https://doi.org/10.1021/acs.jmedchem.4c00121

TY - JOUR

T1 - Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor

AU - Xiong, Yan

AU - Greschik, Holger

AU - Johansson, Catrine

AU - Seifert, Ludwig

AU - Gamble, Vicki

AU - Park, Kwang Su

AU - Fagan, Vincent

AU - Li, Fengling

AU - Chau, Irene

AU - Vedadi, Masoud

AU - Arrowsmith, Cheryl H.

AU - Brennan, Paul

AU - Fedorov, Oleg

AU - Jung, Manfred

AU - Farnie, Gillian

AU - Liu, Jing

AU - Oppermann, Udo

AU - Schüle, Roland

AU - Jin, Jian

PY - 2024/4/11

Y1 - 2024/4/11

N2 - 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.

AB - 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.

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U2 - 10.1021/acs.jmedchem.4c00121

DO - 10.1021/acs.jmedchem.4c00121

M3 - Article

AN - SCOPUS:85189026229

SN - 0022-2623

VL - 67

SP - 5837

EP - 5853

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

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

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