Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1)
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, select...
| Egile Nagusiak: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formatua: | Journal article |
| Hizkuntza: | English |
| Argitaratua: |
American Chemical Society
2019
|
| _version_ | 1826268309621833728 |
|---|---|
| author | Xiong, Y Greschik, H Johansson, C Seifert, L Bacher, J Park, K Babault, N Martini, M Fagan, V Li, F Chau, I Christott, T Dilworth, D Barsyte-Lovejoy, D Vedadi, M Arrowsmith, C Brennan, P Fedorov, O Jung, M Farnie, G Liu, J Oppermann, U Schüle, R Jin, J |
| author_facet | Xiong, Y Greschik, H Johansson, C Seifert, L Bacher, J Park, K Babault, N Martini, M Fagan, V Li, F Chau, I Christott, T Dilworth, D Barsyte-Lovejoy, D Vedadi, M Arrowsmith, C Brennan, P Fedorov, O Jung, M Farnie, G Liu, J Oppermann, U Schüle, R Jin, J |
| author_sort | Xiong, Y |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:07:42Z |
| format | Journal article |
| id | oxford-uuid:3d071394-ac78-46e4-b5a4-2c8a8f713183 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:07:42Z |
| publishDate | 2019 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:3d071394-ac78-46e4-b5a4-2c8a8f7131832022-03-26T14:17:13ZDiscovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3d071394-ac78-46e4-b5a4-2c8a8f713183EnglishSymplectic Elements at OxfordAmerican Chemical Society2019Xiong, YGreschik, HJohansson, CSeifert, LBacher, JPark, KBabault, NMartini, MFagan, VLi, FChau, IChristott, TDilworth, DBarsyte-Lovejoy, DVedadi, MArrowsmith, CBrennan, PFedorov, OJung, MFarnie, GLiu, JOppermann, USchüle, RJin, JBy 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. |
| spellingShingle | Xiong, Y Greschik, H Johansson, C Seifert, L Bacher, J Park, K Babault, N Martini, M Fagan, V Li, F Chau, I Christott, T Dilworth, D Barsyte-Lovejoy, D Vedadi, M Arrowsmith, C Brennan, P Fedorov, O Jung, M Farnie, G Liu, J Oppermann, U Schüle, R Jin, J Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title | Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title_full | Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title_fullStr | Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title_full_unstemmed | Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title_short | Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) |
| title_sort | discovery of a potent and selective fragment like inhibitor of methyllysine reader protein spindlin 1 spin1 |
| work_keys_str_mv | AT xiongy discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT greschikh discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT johanssonc discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT seifertl discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT bacherj discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT parkk discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT babaultn discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT martinim discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT faganv discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT lif discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT chaui discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT christottt discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT dilworthd discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT barsytelovejoyd discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT vedadim discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT arrowsmithc discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT brennanp discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT fedorovo discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT jungm discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT farnieg discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT liuj discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT oppermannu discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT schuler discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 AT jinj discoveryofapotentandselectivefragmentlikeinhibitorofmethyllysinereaderproteinspindlin1spin1 |