molecular analysis of the interplay between all …

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

3

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

13

ReplicaEvestress/DNAdamageinducedbyHDACi

Noacketal.,ArchivesofToxicology,201713

14

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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