Suppression of HDAC nuclear export and cardiomyocyte hypertrophy by novel irreversible inhibitors of CRM1.
Histone deacetylase 5 (HDAC5) represses expression of nuclear genes that promote cardiac hypertrophy. Agonism of a variety of G protein coupled receptors (GPCRs) triggers phosphorylation-dependent nuclear export of HDAC5 via the CRM1 nuclear export receptor, resulting in derepression of pro-hypertrophic genes. A cell-based high-throughput screen of a commercial compound collection was employed to identify compounds with the ability to preserve the nuclear fraction of GFP-HDAC5 in primary cardiomyocytes exposed to GPCR agonists. A hit compound potently inhibited agonist-induced GFP-HDAC5 nuclear export in cultured neonatal rat ventricular myocytes (NRVMs). A small set of related compounds was designed and synthesized to evaluate structure-activity relationship (SAR). The results demonstrated that inhibition of HDAC5 nuclear export was a result of compounds irreversibly reacting with a key cysteine residue in CRM1 that is required for its function. CRM1 inhibition by the compounds also resulted in potent suppression of cardiomyocyte hypertrophy. These studies define a novel class of anti-hypertrophic compounds that function through irreversible inhibition of CRM1-dependent nuclear export.
Novartis Institutes for Biomedical Research, USA. Lauren.monovich@novartis.com
Lauren
L
Monovich
Keith A
KA
Koch
Robin
R
Burgis
Ekundayo
E
Osimboni
Thierry
T
Mann
Daniel
D
Wall
Jinhai
J
Gao
Yan
Y
Feng
Richard B
RB
Vega
Benjamin A
BA
Turner
David B
DB
Hood
Andy
A
Law
Philip J
PJ
Papst
David
D
Koditek
Joseph A
JA
Chapo
Brian G
BG
Reid
Lawrence S
LS
Melvin
Nikos C
NC
Pagratis
Timothy A
TA
McKinsey
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000577:Amides / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097606:Exportin 1 Protein
D000577:Amides; D000814:Aniline Compounds; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C498619:Hdac5 protein, rat