molecular analysis of the interplay between all …
TRANSCRIPT
MOLECULARANALYSISOFTHEINTERPLAYBETWEENALL-TRANSRETINOICACIDANDHISTONEDEACETYLASEINHIBITORSIN
ACUTEPROMYELOCYTICLEUKEMIACELLS
Prof.Dr.OliverH.KrämerIns4tuteofToxicology
UniversityMedicalCenter
APLMee4ngRomeSept.20171
DisclosuresPatentsTheuseofmolecularmarkersforthepreclinicalandclinicalprofilingofinhibitorsofenzymeshavinghistonedeacetylaseac:vity(WO/2004/027418).NovelHDAC6inhibitorsandtheiruses(EP14179728.2,WO2013/062344A1).
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1. The use of molecular markers for the preclinical and clinical profiling of inhibitors of enzymes having histone deacetylase activity (WO/2004/027418). 2. Novel HDAC6 inhibitors and their uses (EP 14179728.2, WO 2013/062344 A1).
Europäisches Patent: Novel HDAC6 inhibitors and their uses, EP 14179728.2, WO 2013/062344 A1); European Patent; internationale Patentanmeldung erfolgte 2017.
Angemeldet: Synthesis, Pharmacology and use of New and Selective FMS-like tyrosine kinase 3 (FLT3) FLT3 Inhibitors.
Mainz, 15.04.2017
APLpaEent
Combina:onsofATRAandHDACishouldimprovethesuccessofAPLtreatment.
AltucciandGronemeyer,NatRevCancer,2001
PML-RARα:SensiEvetoRAandassociatedwithHDACs
HDACi
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4
HDACs:Zn2+-dependentremovalofacetylgroups&HDACi
Hennigetal.,Br.J.ofCancer,20154
5
Treatmentscheme:NB4cells
Hennigetal.,Br.J.ofCancer,20155
ATRApre-treatmentprotectsfromVPA-inducedapoptosis
0
5
10
15
20
CTL A48h V24h (A+V)24h A48 h + V24h
SubG
1%
*n.s.
ATRA1µM,VPA1.5mMHennigetal.,Br.J.ofCancer,2015 6
Pan-HDACiovercomeprotecEveeffectofATRA
ATRA1µM
MS-275-HDACiinhibitsHDAC1-3VPA-HDACiinhibitsclassIHDACsLBH589-pan-HDACiinhibitsallZn2+-dependentHDACs
Hennigetal.,Br.J.ofCancer,2015
7
SAHAvsFK228
Noacketal.,ArchivesofToxicology,2017 8
SAHA-pan-HDACiinhibitsallZn2+-dependentHDACs
FK228vsSAHA
Noacketal.,ArchivesofToxicology,2017 9
FK228-HDACiinhibitsHDAC1-3
FK228vsSAHA
Noacketal.,ArchivesofToxicology,2017 10
HDACiaffinityiscriEcaltoovercomeprotecEveeffectsofATRA
Noacketal.,ArchivesofToxicology,2017 11
HDACiaffinityiscriEcaltoovercomeprotecEveeffectsofATRA
Noacketal.,ArchivesofToxicology,2017 12
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ReplicaEvestress/DNAdamageinducedbyHDACi
Noacketal.,ArchivesofToxicology,201713
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ReplicaEvestress/DNAdamageinducedbyHDACi
Noacketal.,ArchivesofToxicology,201714
LBH-589
BCL-xL
ATRApre-treatment
MS-275
VPA
DNAdamageandapoptosissurvival
++
C/EBPɛ BCL-xL C/EBPɛ
differenEaEon/inducEonofC/EBPs
Hennigetal.,Br.J.ofCancer,2015 Noacketal.,ArchivesofToxicology,2017
FK228
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SAHA
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Conclusions
! ATRAinducesresistanceagainstHDACidependingontheiraffinity
! noclearbenefitofATRA/HDACico-treatment! Hyperacetyla:onofhistonesasmarkerforsensi:vitytoATRA-mediatedsurvival
! BothapoptosisandDNAdamageinduc:ondependonHDACiaffinity,notclassspecificity
! IfHDACi/ATRAcombina:onsareused,ratheruseHDACiwithhighaffinity,maybeavoidATRAcotreatment
! PoorclinicalsuccessofcertainATRA/HDACicombina:onsclearlymirroredbyinvitroexperimentswithNB4cells
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AcknowledgementThankyouforyouraben:on!
Groupleader: KooperaEonpartners:Prof.O.H.Krämer Prof.SiavoshMahboobi
Dr.AndreasSellmerPhDStudents: Univ.ofRegensburgMandyBeyer (Marbostat-100)NicoleKiweler NisinthaMahendrarajah ThorstenHeinzelAnjaGöder DorleHennigMiriamPons KatrinNoackAl-HassanAbdeen Univ.ofJenaSvenHenningerTechnicalAssistance:Chris:naBrachei
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