8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2016
|
| _version_ | 1797055132260630528 |
|---|---|
| author | Bavetsias, V Lanigan, R Ruda, G Atrash, B McLaughlin, M Tumber, A Mok, N Le Bihan, Y Dempster, S Boxall, K Jeganathan, F Hatch, S Savitsky, P Velupillai, S Krojer, T England, K Sejberg, J Thai, C Donovan, A Pal, A Scozzafava, G Bennett, J Kawamura, A Johansson, C Szykowska, A Gileadi, C Burgess-Brown, N von Delft, F Oppermann, U Walters, Z Shipley, J Raynaud, F Westaway, S Prinjha, R Fedorov, O Burke, R Schofield, C Westwood, I Bountra, C Müller, S van Montfort, R Brennan, P Blagg, J |
| author_facet | Bavetsias, V Lanigan, R Ruda, G Atrash, B McLaughlin, M Tumber, A Mok, N Le Bihan, Y Dempster, S Boxall, K Jeganathan, F Hatch, S Savitsky, P Velupillai, S Krojer, T England, K Sejberg, J Thai, C Donovan, A Pal, A Scozzafava, G Bennett, J Kawamura, A Johansson, C Szykowska, A Gileadi, C Burgess-Brown, N von Delft, F Oppermann, U Walters, Z Shipley, J Raynaud, F Westaway, S Prinjha, R Fedorov, O Burke, R Schofield, C Westwood, I Bountra, C Müller, S van Montfort, R Brennan, P Blagg, J |
| author_sort | Bavetsias, V |
| collection | OXFORD |
| description | We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay. |
| first_indexed | 2024-03-06T19:06:50Z |
| format | Journal article |
| id | oxford-uuid:156ed4f4-b511-480b-b76a-f73cf4960a12 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:06:50Z |
| publishDate | 2016 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:156ed4f4-b511-480b-b76a-f73cf4960a122022-03-26T10:25:33Z8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:156ed4f4-b511-480b-b76a-f73cf4960a12EnglishSymplectic Elements at OxfordAmerican Chemical Society2016Bavetsias, VLanigan, RRuda, GAtrash, BMcLaughlin, MTumber, AMok, NLe Bihan, YDempster, SBoxall, KJeganathan, FHatch, SSavitsky, PVelupillai, SKrojer, TEngland, KSejberg, JThai, CDonovan, APal, AScozzafava, GBennett, JKawamura, AJohansson, CSzykowska, AGileadi, CBurgess-Brown, Nvon Delft, FOppermann, UWalters, ZShipley, JRaynaud, FWestaway, SPrinjha, RFedorov, OBurke, RSchofield, CWestwood, IBountra, CMüller, Svan Montfort, RBrennan, PBlagg, JWe report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay. |
| spellingShingle | Bavetsias, V Lanigan, R Ruda, G Atrash, B McLaughlin, M Tumber, A Mok, N Le Bihan, Y Dempster, S Boxall, K Jeganathan, F Hatch, S Savitsky, P Velupillai, S Krojer, T England, K Sejberg, J Thai, C Donovan, A Pal, A Scozzafava, G Bennett, J Kawamura, A Johansson, C Szykowska, A Gileadi, C Burgess-Brown, N von Delft, F Oppermann, U Walters, Z Shipley, J Raynaud, F Westaway, S Prinjha, R Fedorov, O Burke, R Schofield, C Westwood, I Bountra, C Müller, S van Montfort, R Brennan, P Blagg, J 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title | 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title_full | 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title_fullStr | 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title_full_unstemmed | 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title_short | 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors |
| title_sort | 8 substituted pyrido 3 4 d pyrimidin 4 3h one derivatives as potent cell permeable kdm4 jmjd2 and kdm5 jarid1 histone lysine demethylase inhibitors |
| work_keys_str_mv | AT bavetsiasv 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT laniganr 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT rudag 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT atrashb 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT mclaughlinm 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT tumbera 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT mokn 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT lebihany 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT dempsters 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT boxallk 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT jeganathanf 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT hatchs 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT savitskyp 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT velupillais 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT krojert 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT englandk 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT sejbergj 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT thaic 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT donovana 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT pala 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT scozzafavag 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT bennettj 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT kawamuraa 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT johanssonc 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT szykowskaa 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT gileadic 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT burgessbrownn 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT vondelftf 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT oppermannu 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT waltersz 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT shipleyj 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT raynaudf 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT westaways 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT prinjhar 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT fedorovo 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT burker 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT schofieldc 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT westwoodi 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT bountrac 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT mullers 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT vanmontfortr 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT brennanp 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors AT blaggj 8substitutedpyrido34dpyrimidin43honederivativesaspotentcellpermeablekdm4jmjd2andkdm5jarid1histonelysinedemethylaseinhibitors |