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@ARTICLE{Xiong:289139,
author = {Y. Xiong and H. Greschik and C. Johansson and L. Seifert
and V. Gamble and K.-S. Park and V. Fagan and F. Li and I.
Chau and M. Vedadi and C. H. Arrowsmith and P. Brennan and
O. Fedorov and M. Jung$^*$ and G. Farnie and J. Liu and U.
Oppermann and R. Schüle and J. Jin},
title = {{D}iscovery of a {P}otent, {S}elective, and {C}ell-{A}ctive
{SPIN}1 {I}nhibitor.},
journal = {Journal of medicinal chemistry},
volume = {67},
number = {7},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {DKFZ-2024-00606},
pages = {5837-5853},
year = {2024},
note = {2024 Apr 11;67(7):5837-5853},
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.},
cin = {FR01},
ddc = {610},
cid = {I:(DE-He78)FR01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38533580},
doi = {10.1021/acs.jmedchem.4c00121},
url = {https://inrepo02.dkfz.de/record/289139},
}