Page 7 of 7
ACS Medicinal Chemistry Letters
atꢀ theꢀ Carboxy-Termainlꢀ Conservedꢀ Domainꢀ byꢀ Transcriptionalꢀ
Co-ActivatorꢀP300.ꢀOncogeneꢀ2000,ꢀ19,ꢀ444-451.ꢀ
9)ꢀ Kim,ꢀ J.ꢀ H.;ꢀ Cho,ꢀ E.ꢀ J.;ꢀ Kim,ꢀ S.ꢀ T.;ꢀ Youn,ꢀ H.ꢀ D.ꢀ CtBPꢀ Repressesꢀ
p300-Mediatedꢀ Transcriptionalꢀ Activationꢀ byꢀ Directꢀ Associationꢀ
withꢀitsꢀBromodomain.ꢀNat. Struct. Mol. Biol.ꢀ2005,ꢀ12,ꢀ423-428.ꢀ
(22)ꢀ Picaud,ꢀ S.;ꢀ Fedorov,ꢀ O.;ꢀ Thanasopoulou,ꢀ A.;ꢀ Leonards,ꢀ K.;ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Jones,ꢀK.;ꢀMeier,ꢀJ.;ꢀOlzscha,ꢀH.;ꢀMonteiro,ꢀO.;ꢀMartin,ꢀS.;ꢀPhilpott,ꢀ
M.;ꢀTumber,ꢀA.;ꢀFilippakopoulos,ꢀP.;ꢀYapp,ꢀC.;ꢀWells,ꢀC.;ꢀChe,ꢀK.ꢀH.;ꢀ
Bannister,ꢀ A.;ꢀ Robson,ꢀ S.;ꢀ Kumar,ꢀ U.;ꢀ Parr,ꢀ N.;ꢀ Lee,ꢀ K.;ꢀ Lugo,ꢀ D.;ꢀ
Jeffrey,ꢀ P.;ꢀ Taylor,ꢀ S.;ꢀ Vecellio,ꢀ M.ꢀ L.;ꢀ Bountra,ꢀ C.;ꢀ Brennan,ꢀ P.ꢀ E.;ꢀ
O'Mahony,ꢀA.;ꢀVelichko,ꢀS.;ꢀMüller,ꢀS.;ꢀHay,ꢀD.;ꢀDaniels,ꢀD.ꢀL.;ꢀUrh,ꢀ
M.;ꢀ Laꢀ Thangue,ꢀ N.ꢀ B.;ꢀ Kouzarides,ꢀ T.;ꢀ Prinjha,ꢀ R.;ꢀ Schwaller,ꢀ J.;ꢀ
Knapp,ꢀS.ꢀGenerationꢀofꢀaꢀSelectiveꢀSmallꢀMoleculeꢀInhibitorꢀofꢀtheꢀ
CBP/p300ꢀ Bromodomainꢀ forꢀ Leukemiaꢀ Therapy.ꢀ Cancer Res.ꢀ
2015,ꢀ75,ꢀ5106-5119.ꢀ
(23)ꢀPiatnitskiꢀChekler,ꢀE.ꢀL.;ꢀPellegrino,ꢀJ.ꢀA.;ꢀLanz,ꢀT.ꢀA.;ꢀDenny,ꢀR.ꢀ
A.;ꢀFlick,ꢀA.ꢀC.;ꢀCoe,ꢀJ.;ꢀLangille,ꢀJ.;ꢀBasak,ꢀA.;ꢀLiu,ꢀS.;ꢀStock,ꢀI.ꢀA.;ꢀSa-
hasrabudhe,ꢀP.;ꢀBonin,ꢀP.ꢀD.;ꢀLee,ꢀK.;ꢀPletcher,ꢀM.ꢀT.;ꢀJones,ꢀL.ꢀH.ꢀ
Transcriptionalꢀ Profilingꢀ ofꢀ aꢀ Selectiveꢀ CREBꢀ Bindingꢀ Proteinꢀ
Bromodomainꢀ Inhibitorꢀ Highlightsꢀ Therapeuticꢀ Opportunities.ꢀ
Chemistry and Biologyꢀ2015,ꢀ22,ꢀ1588-1596.ꢀ
(24)ꢀ Unzue,ꢀ A.;ꢀ Xu,ꢀ M.;ꢀ Dong,ꢀ J.;ꢀWiedmer,ꢀ L.;ꢀ Spiliotopoulos,ꢀ D.;ꢀ
Caflish,ꢀA.;ꢀNevado,ꢀC.ꢀFragment-BasedꢀDesignꢀofꢀSelectiveꢀNano-
molarꢀLigandsꢀofꢀtheꢀCREBBPꢀBromodomain.ꢀJ. Med. Chem.ꢀ2015,ꢀ
ASAPꢀonline.ꢀ
(25)ꢀPantoliano,ꢀM.ꢀW.;ꢀPetrella,ꢀE.ꢀC.;ꢀKwasnoski,ꢀJ.ꢀD.;ꢀLobanov,ꢀV.ꢀ
S.;ꢀMyslik,ꢀJ.;ꢀGraf,ꢀE.;ꢀCarver,ꢀT.;ꢀAsel,ꢀE.;ꢀSpringer,ꢀB.ꢀA.;ꢀLane,ꢀP.;ꢀ
Salemme,ꢀF.ꢀR.ꢀHigh-DensityꢀMiniaturizedꢀThermalꢀShiftꢀAssaysꢀasꢀ
aꢀGeneralꢀStrategyꢀforꢀDrugꢀDiscovery.ꢀJ. Biomol. Screen.ꢀ2001,ꢀ6,ꢀ
429-440.ꢀ
(
(
10)ꢀPetrij,ꢀF.;ꢀGiles,ꢀR.ꢀH.;ꢀDauwerse,ꢀH.ꢀG.;ꢀSaris,ꢀJ.ꢀJ.;ꢀHennekam,ꢀ
R.ꢀC.;ꢀMasuno,ꢀM.;ꢀTommerup,ꢀN.;ꢀvanꢀOmmen,ꢀG.ꢀJ.;ꢀGoodman,ꢀR.ꢀ
H.;ꢀ Peters,ꢀ D.ꢀ J.;ꢀ Breuning,ꢀ M.ꢀ H.ꢀ Rubinstein-Taybiꢀ syndromeꢀ
Causedꢀ byꢀ Mutationsꢀ inꢀ theꢀ Transcriptionalꢀ Co-Activatorꢀ CBP.ꢀ
Natureꢀ1995,ꢀ376,ꢀ348-351.ꢀ
(
11)ꢀKung,ꢀA.ꢀL.;ꢀRebel,ꢀV.ꢀI.;ꢀBronson,ꢀR.ꢀT.;ꢀCh’ng,ꢀL-E.;ꢀSieff,ꢀC.ꢀA.;ꢀ
Livingston,ꢀD.ꢀM.;ꢀYao,ꢀT-P.ꢀGeneꢀDose-DependentꢀControlꢀofꢀHem-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
atopoisisꢀandꢀHematologicꢀTumorꢀSuppressionꢀbyꢀCBP.ꢀGenes Dev.ꢀ
2
000,ꢀ14,ꢀ272-277.ꢀ
(12)ꢀRebel,ꢀV.ꢀI.;ꢀKung,ꢀA.ꢀL.;ꢀTanner,ꢀE.ꢀA.;ꢀYang,ꢀH.;ꢀBronson,ꢀR.ꢀT.;ꢀ
Livingston,ꢀ D.ꢀ M.ꢀ Distinctꢀ Rolesꢀ forꢀ CREB-Bindingꢀ Proetinꢀ andꢀ
P300ꢀinꢀHematopoieticꢀStemꢀCellꢀSelf-Renewal.ꢀ Proc. Natl. Acad.
Sci. U.S.A.ꢀ2002,ꢀ99,ꢀ14789-14794.ꢀ
(
13)ꢀGiles,ꢀR.ꢀH.;ꢀPeters,ꢀD.ꢀJ.;ꢀBreuning,ꢀM.ꢀH.ꢀConjunctionꢀDysfunc-
tion:ꢀCBP/P300ꢀinꢀHumanꢀDisease.ꢀTrends Genet.ꢀ1998,ꢀ14,ꢀ178-
83.ꢀ
1
(14)ꢀLi,ꢀY.;ꢀYang,ꢀH.ꢀX.;ꢀLuo,ꢀR.-Z.;ꢀZhang,ꢀY.;ꢀLi,ꢀM.;ꢀWang,ꢀX.;ꢀJia,ꢀW.ꢀ
H.ꢀHighꢀExpressionꢀofꢀP300ꢀHasꢀAnꢀUnfavorableꢀImpactꢀonꢀSur-
vivalꢀ inꢀ Resectableꢀ Esophagealꢀ Squamousꢀ Cellꢀ Carcinoma.ꢀ Ann.
Thorac. Surg.ꢀ2011,ꢀ91,ꢀ1531-1538.ꢀ
(
15)ꢀLi,ꢀM.;ꢀLuo,ꢀR.-Z.;ꢀChen,ꢀJ.-W.;ꢀCao,ꢀY.;ꢀLu,ꢀJ.-B.;ꢀHe,ꢀJ.-H.;ꢀWu,ꢀQ.-
(26)ꢀ Mertz,ꢀ J.ꢀ A.;ꢀ Conery,ꢀ A.ꢀ R.;ꢀ Bryant,ꢀ A.ꢀ M.;ꢀ Sandy,ꢀ P.;ꢀ Bal-
rd
L.;ꢀCai,ꢀM.-Y.ꢀHighꢀExpressionꢀofꢀTranscriptionalꢀCoactivatorꢀP300ꢀ
CorrelatesꢀwithꢀAggressiveꢀFeaturesꢀandꢀPoorꢀPrognosisꢀofꢀHepa-
tocellularꢀCarcinoma.ꢀJ.ꢀTrans.ꢀMed.ꢀ2011,ꢀ9,ꢀ5.ꢀ
asubramanian,ꢀS.;ꢀMele,ꢀD.ꢀA.;ꢀBergeron,ꢀL.;ꢀSims,ꢀR.ꢀJ.ꢀ3 .ꢀTarget-
ingꢀMYCꢀDependenceꢀinꢀCancerꢀbyꢀInhibitingꢀBETꢀBromodomains.ꢀ
Proc. Natl. Acad. Sci. U.S.A.ꢀ2011,ꢀ108,ꢀ16669.ꢀ
(27)ꢀLLEꢀ=ꢀpIC50ꢀ–ꢀclogP;ꢀShultz,ꢀM.ꢀD.;ꢀTheꢀThermodynamicꢀBasisꢀ
forꢀtheꢀUseꢀofꢀLipophilicꢀEfficiencyꢀ(LipE)ꢀinꢀEnthalpicꢀOptimiza-
tions.ꢀBioorg. Med. Chem. Lett.ꢀ2013,ꢀ23,ꢀ5992-6000.ꢀ
(16)ꢀShigeno,ꢀK.;ꢀYoshida,ꢀH.;ꢀPan,ꢀL.;ꢀLuo,ꢀJ.ꢀM.;ꢀFujisawa,ꢀS.;ꢀNaito,ꢀ
K.;ꢀ Nakamura,ꢀ S.;ꢀ Shinjo,ꢀ K.;ꢀ Takeshita,ꢀ A.;ꢀ Ohno,ꢀ R.;ꢀ Ohnishi,ꢀ K.ꢀ
Disease-RelatedꢀPotentialꢀofꢀMutationsꢀinꢀTranscriptionalꢀCofac-
torsꢀ CREB-Bindingꢀ Proteinꢀ andꢀP300ꢀ inꢀ Leukemias.ꢀ Cancer Lett.ꢀ
(28)ꢀInterestingly,ꢀaꢀbenzodiazepinoneꢀwasꢀrecentlyꢀreportedꢀtoꢀ
inhibitꢀtheꢀfirstꢀbromodomainꢀofꢀBRD4.ꢀAlthoughꢀthatꢀcompoundꢀ
andꢀcompoundꢀ1ꢀbothꢀbindꢀthroughꢀaꢀhydrogen-bondingꢀinterac-
tionꢀwithꢀtheꢀhighlyꢀconservedꢀAsnꢀresidue,ꢀtheirꢀbindingꢀmodesꢀ
areꢀ flipped,ꢀ relativeꢀ toꢀ eachꢀ other.ꢀ Forꢀ details,ꢀ seeꢀ Zhao,ꢀ H.;ꢀ
Gartenmann,ꢀL.;ꢀDong,ꢀJ.;ꢀCaflisch,ꢀA.;ꢀDiscoveryꢀofꢀBRD4ꢀBromo-
domainꢀInhibitorsꢀbyꢀFragment-basedꢀHigh-throughputꢀDocking.ꢀ
Bioorg. Med. Chem. Lett.ꢀ2014,ꢀ24,ꢀ2493-2496.ꢀ
(29)ꢀ Hewings,ꢀ D.ꢀ S.;ꢀ Rooney,ꢀ T.ꢀ P.ꢀ C.;ꢀ Jennings,ꢀ L.ꢀ E.;ꢀ Hay,ꢀ D.ꢀ A.;ꢀ
Schofield,ꢀC.ꢀJ.;ꢀBrennan,ꢀP.ꢀE.;ꢀKnapp,ꢀS.;ꢀConway,ꢀS.ꢀJ.ꢀProgressꢀinꢀ
theꢀDevelopmentꢀandꢀApplicationꢀofꢀSmallꢀMoleculeꢀInhibitorsꢀofꢀ
Bromodomain-acetyl-lysineꢀinteractions.ꢀJ. Med. Chem.ꢀ2012,ꢀ55,ꢀ
9393−9413.ꢀ
(30)ꢀMachleidt,ꢀT.;ꢀWoodroofe,ꢀC.ꢀC.;ꢀSchwinn,ꢀM.ꢀK.;ꢀMendez,ꢀJ.;ꢀ
Robers,ꢀM.ꢀB.;ꢀZimmerman,ꢀK.;ꢀOtto,ꢀP.;ꢀDaniels,ꢀD.ꢀL.;ꢀKirkland,ꢀT.ꢀ
A.;ꢀWood,ꢀK.ꢀV.ꢀNanoBRETꢀ--ꢀAꢀNovelꢀBRETꢀPlatformꢀforꢀtheꢀAnaly-
sisꢀ ofꢀ Protein-Proteinꢀ Interactions.ꢀ ACS Chem. Biol.ꢀ 2015,ꢀ 10,ꢀ
1797-1804.ꢀ
(31)ꢀOurꢀinterestꢀinꢀpursuingꢀmoreꢀpolarꢀcompoundsꢀwasꢀdrivenꢀ
byꢀ ourꢀ consistentꢀ observationꢀ that,ꢀ betweenꢀ twoꢀ compoundsꢀ ofꢀ
comparableꢀCBPꢀpotency,ꢀincreasedꢀpolarityꢀcorrelatedꢀwithꢀbet-
terꢀselectivityꢀoverꢀBRD4ꢀ(dataꢀnotꢀshown).ꢀ
2
004,ꢀ213,ꢀ11-20.ꢀ
(
17)ꢀ Mullighan,ꢀ C.ꢀ G.;ꢀ Zhang,ꢀ J.;ꢀKasper,ꢀ L.ꢀ H.;ꢀ Lerach,ꢀ S.;ꢀ Payne-
Turner,ꢀ D.;ꢀ Phillips,ꢀ L.ꢀ A.;ꢀ Heatley,ꢀ s.ꢀ L.;ꢀ Holmfeldt,ꢀ L.;ꢀ Collines-
Underwood,ꢀ J.ꢀ R.;ꢀ Ma,ꢀ J.;ꢀ Buetow,ꢀ K.ꢀ H.;ꢀ Pui,ꢀ C.ꢀ H.;ꢀ Baker,ꢀ S.ꢀ D.;ꢀ
Brindle,ꢀP.ꢀK.;ꢀDowning,ꢀJ.ꢀR.;ꢀCREBBPꢀMutationsꢀinꢀRelapsedꢀAcuteꢀ
LymphoblasticꢀLeukaemia.ꢀNatureꢀ2011,ꢀ471,ꢀ235-239.ꢀ
(
18)ꢀKishimoto,ꢀM.;ꢀKohno,ꢀT.;ꢀOkudela,ꢀK.;ꢀOtsuka,ꢀA.;ꢀSasaki,ꢀH.;ꢀ
Tanabe,ꢀC.;ꢀSakiyama,ꢀT.;ꢀHirama,ꢀC.;ꢀKitabayashi,ꢀI.;ꢀMinna,ꢀJ.ꢀD.;ꢀ
Takenoshita,ꢀS.;ꢀYokota,ꢀJ. Clin. Cancer Res.ꢀ2005,ꢀ11,ꢀ512-510.ꢀ
(19)ꢀPasqualucci,ꢀL.ꢀDominquez-Sola,ꢀD.;ꢀChiarenz,ꢀA.;ꢀFabbri,ꢀG.;ꢀ
Grunn,ꢀA.;ꢀTrifonov,ꢀV.;ꢀKasper,ꢀL.ꢀH.;ꢀLerach,ꢀS.;ꢀTang,ꢀH.;ꢀMa,ꢀJ.;ꢀ
Rossi,ꢀD.;ꢀChadburn,ꢀA.;ꢀMurtyꢀV.ꢀV.;ꢀMullighan,ꢀC.ꢀG.;ꢀGaidano,ꢀG.;ꢀ
Rabadan,ꢀR.;ꢀBrindle,ꢀP.ꢀK.;ꢀDalla-Favera,ꢀR.ꢀInactivatingꢀMutationsꢀ
ofꢀ Acetyltransferaseꢀ Genesꢀ inꢀ B-Cellꢀ Lymphoma.ꢀ Nature,ꢀ 2011,ꢀ
4
71,ꢀ189-195.ꢀ
(20)ꢀHuether,ꢀR.;ꢀDong,ꢀL.;ꢀChen,ꢀX.;ꢀWu,ꢀG.;ꢀParker,ꢀM.;ꢀWei,ꢀL.;ꢀMa,ꢀ
J.;ꢀEdmonson,ꢀM.ꢀN.;ꢀHedlund,ꢀE.ꢀK.;ꢀRusch,ꢀM.ꢀC.;ꢀShurtleff,ꢀS.ꢀA.;ꢀ
Mulder,ꢀ H.ꢀ L.;ꢀ Boggs,ꢀ K.;ꢀ Vadordaria,ꢀ B.;ꢀ Cheng,ꢀ J.;ꢀ Yergeau,ꢀ D.;ꢀ
Song,ꢀ G.;ꢀ Becksfort,ꢀ J.;ꢀ Lemmon,ꢀ G.;ꢀ Weber,ꢀ C.;ꢀ Cai,ꢀ Z.;ꢀ Dang,ꢀ J.;ꢀ
Walsh,ꢀM.;ꢀGedman,ꢀA.ꢀL.;ꢀFaber,ꢀZ.;ꢀEaston,ꢀJ.;ꢀGruber,ꢀT.;ꢀKriwacki,ꢀ
R.ꢀ W.;ꢀ Partridge,ꢀ J.ꢀ F.;ꢀ Ding,ꢀ L.;ꢀWilson,ꢀ R.ꢀ K.;ꢀ Mardis,ꢀE.ꢀ R.;ꢀ Mul-
lighan,ꢀC.ꢀG.;ꢀGilbertson,ꢀR.ꢀJ.;ꢀBaker,ꢀS.ꢀJ.;ꢀZambetti,ꢀG.;ꢀEllison,ꢀD.ꢀ
W.;ꢀZhang,ꢀJ.;ꢀDowning,ꢀJ.ꢀR.ꢀTheꢀLanscapeꢀofꢀSomaticꢀMutationsꢀinꢀ
Epigeneticꢀ Regulatorsꢀ acrossꢀ 1,000ꢀ Paediatricꢀ Cancerꢀ Genomes.ꢀ
Nat. Commun.ꢀ2014,ꢀ5,ꢀ3630.ꢀ
(32)ꢀConery,ꢀA.ꢀR.;ꢀCentore,ꢀR.ꢀC.;ꢀNeiss,ꢀA.;ꢀKeller,ꢀP.ꢀJ.;ꢀJoshi,ꢀS.;ꢀ
Spillane,ꢀK.ꢀL.;ꢀSandy,ꢀP.;ꢀHatton,ꢀC.;ꢀPardo,ꢀE.;ꢀZawadzke,ꢀL.;ꢀBom-
mi-Reddy,ꢀA.;ꢀGascoigne,ꢀK.ꢀE.;ꢀBryant,ꢀB.ꢀM.;ꢀMertz,ꢀJ.ꢀA.;ꢀSims,ꢀR.ꢀJ.ꢀ
3rd.ꢀBromodomainꢀInhibitionꢀofꢀtheꢀTranscriptionalꢀCoactivatorsꢀ
CBP/EP300ꢀasꢀaꢀTherapeuticꢀStrategyꢀtoꢀTargetꢀtheꢀIRF4ꢀNetworkꢀ
inꢀMultipleꢀMyeloma.ꢀ
(
21)ꢀBunnage,ꢀM.ꢀE.;ꢀPiatnitskiꢀChekler,ꢀE.ꢀL.;ꢀJones,ꢀL.ꢀH.ꢀTargetꢀ
ValidationꢀUsingꢀChemicalꢀProbes.ꢀNature Chemical Biology,ꢀ2013,ꢀ
,ꢀ195-199.ꢀ
9
ꢀ
ACS Paragon Plus Environment