Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors

Agarwal, Rupesh; Pattarawat, Pawat; Duff, Michael R.; Wang, Hwa-Chain Robert; Baudry, Jerome; Smith, Jeremy C.

doi:10.3390/ph17070867

Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors

Journal Article · Tue Jul 02 00:00:00 EDT 2024 · Pharmaceuticals

DOI:https://doi.org/10.3390/ph17070867· OSTI ID:2406739

^[1]; Pattarawat, Pawat ^[2]; Duff, Michael R. ^[3]; ^[2]; Baudry, Jerome ^[4]; ^[1]

Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States). College of Veterinary Medicine
Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Alabama, Huntsville, AL (United States)

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2406739

Journal Information:: Pharmaceuticals, Journal Name: Pharmaceuticals Journal Issue: 7 Vol. 17; ISSN 1424-8247

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
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Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors

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