TY - JOUR
T1 - Kinetic Tuning of HDAC Inhibitors Affords Potent Inducers of Progranulin Expression
AU - Moreno-Yruela, Carlos
AU - Fass, Daniel M.
AU - Cheng, Chialin
AU - Herz, Joachim
AU - Olsen, Christian A.
AU - Haggarty, Stephen J.
N1 - Funding Information:
This work was supported by the University of Copenhagen (Ph.D. fellowship for C.M.-Y.), the Lundbeck Foundation (R289-2018-2074, C.A.O.), the Bluefield Project to Cure FTD (S.J.H., J.H.), the National Institute of Neurological Disorders & Stroke (R01NS108115, S.J.H., J.H.), the National Institutes of Health (R37 HL63762, R01 NS093382, R01 NS108115, and RF1 AG053391, J.H.), the Brighfocus Foundation (J.H.), the Harrington Scholar Innovator Award (J.H.), and the Stuart & Suzanne Steele MGH Research Scholars Program (S.J.H.). Travel grants were provided by the University of Copenhagen (Drug Research Academy, C.M.-Y.) and Dagmar Marshalls Fond (C.M.-Y.).
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/8/21
Y1 - 2019/8/21
N2 - Histone deacetylases (HDACs) are enzymes involved in the epigenetic control of gene expression. A handful of HDAC inhibitors have been approved for the treatment of cancer, and HDAC inhibition has also been proposed as a novel therapeutic strategy for neurodegenerative disorders. These disorders include progranulin (PGRN)-deficient forms of frontotemporal dementia caused by mutations in the GRN gene that lead to haploinsufficiency. Hydroxamic-acid-based inhibitors of HDACs 1-3, reported to have fast-on/fast-off binding kinetics, induce increased expression of PGRN in human neuronal models, while the benzamide class of slow-binding HDAC inhibitors does not produce this effect. These observations indicate that the kinetics of HDAC inhibitor binding can be tuned for optimal induction of human PGRN expression in neurons. Here, we further expand on these findings using human cortical-like, glutamatergic neurons. We provide evidence that two prototypical, potent hydroxamic acid HDAC inhibitors that induce PGRN (panobinostat and trichostatin A) exhibit an initial fast-binding step followed by a second, slower step, referred to as mechanism B of slow binding, rather than simpler fast-on/fast-off binding kinetics. In addition, we show that trapoxin A, a macrocyclic, epoxyketone-containing class I HDAC inhibitor, exhibits slow binding with high, picomolar potency and also induces PGRN expression in human neurons. Finally, we demonstrate induction of PGRN expression by fast-on/fast-off, highly potent, macrocyclic HDAC inhibitors with ethyl ketone or ethyl ester Zn2+ binding groups. Taken together, these data expand our understanding of HDAC1-3 inhibitor binding kinetics, and further delineate the specific combinations of structural and kinetic features of HDAC inhibitors that are optimal for upregulating PGRN expression in human neurons and thus may have translational relevance in neurodegenerative disease.
AB - Histone deacetylases (HDACs) are enzymes involved in the epigenetic control of gene expression. A handful of HDAC inhibitors have been approved for the treatment of cancer, and HDAC inhibition has also been proposed as a novel therapeutic strategy for neurodegenerative disorders. These disorders include progranulin (PGRN)-deficient forms of frontotemporal dementia caused by mutations in the GRN gene that lead to haploinsufficiency. Hydroxamic-acid-based inhibitors of HDACs 1-3, reported to have fast-on/fast-off binding kinetics, induce increased expression of PGRN in human neuronal models, while the benzamide class of slow-binding HDAC inhibitors does not produce this effect. These observations indicate that the kinetics of HDAC inhibitor binding can be tuned for optimal induction of human PGRN expression in neurons. Here, we further expand on these findings using human cortical-like, glutamatergic neurons. We provide evidence that two prototypical, potent hydroxamic acid HDAC inhibitors that induce PGRN (panobinostat and trichostatin A) exhibit an initial fast-binding step followed by a second, slower step, referred to as mechanism B of slow binding, rather than simpler fast-on/fast-off binding kinetics. In addition, we show that trapoxin A, a macrocyclic, epoxyketone-containing class I HDAC inhibitor, exhibits slow binding with high, picomolar potency and also induces PGRN expression in human neurons. Finally, we demonstrate induction of PGRN expression by fast-on/fast-off, highly potent, macrocyclic HDAC inhibitors with ethyl ketone or ethyl ester Zn2+ binding groups. Taken together, these data expand our understanding of HDAC1-3 inhibitor binding kinetics, and further delineate the specific combinations of structural and kinetic features of HDAC inhibitors that are optimal for upregulating PGRN expression in human neurons and thus may have translational relevance in neurodegenerative disease.
KW - Epigenetic
KW - histone deacetylase
KW - kinetic profiling
KW - panobinostat
KW - progranulin
KW - slow-binding inhibitor
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U2 - 10.1021/acschemneuro.9b00281
DO - 10.1021/acschemneuro.9b00281
M3 - Article
C2 - 31330099
AN - SCOPUS:85070935224
SN - 1948-7193
VL - 10
SP - 3769
EP - 3777
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 8
ER -