Carboxamide-Bearing Panobinostat Analogues Designed To Interact with E103-D104 at the Cavity Opening of Class I HDAC Isoforms.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-02 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00494

Callum A Rosser, Samuel V Feeney, Lukas Roth, David E Hibbs, Michael P Gotsbacher, Rachel Codd

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Abstract

Panobinostat (1) inhibits Zn(II)-dependent histone deacetylases (HDACs) which are validated cancer targets. Three sets of 1 analogues containing carboxamide groups designed to form hydrogen bonds with acidic residues (E103, D104) in the cavity opening of a subset of class I isoforms were synthesized and evaluated against HDAC2. All 1 analogues (IC₅₀ range: 150-3320 nM) were less potent HDAC2 inhibitors than 1 (IC₅₀ = 5 nM). Ensemble docking showed that the carboxamide NH₂ group in the most potent 1 analogues S-3 (IC₅₀ = 150 nM) and S-2 (IC₅₀ = 350 nM) enabled hydrogen bond formation with E103 and D104. The proximity of the electron withdrawing carboxamide to the secondary amine in the 1 analogues reduced calculated pK _a values, compared to 1. Reduced electrostatic binding capacity of the 1 analogues, together with solvation and steric penalties, was proposed to negate the binding energy benefit of increased hydrogen bonding. Ensemble docking suggested isoform selectivity as unlikely.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.