Discovery of First-in-Class BAZ2A/B and BAZ2B-Selective Degraders

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-07 DOI:10.1021/acsmedchemlett.4c0033410.1021/acsmedchemlett.4c00334

Leonardo Palaferri, Iván Cheng-Sánchez, Katherine Gosselé, Dominika Zielinska and Cristina Nevado*,

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Abstract

Bromodomain adjacent to zinc finger 2A and 2B (BAZ2A and BAZ2B) are homologous proteins that serve as regulatory subunits in different initiation switch complexes. Despite their structural similarity, BAZ2A/B seem to play different roles in disease development. However, reported BAZ2A/B inhibitors bind similarly to both homologues. Here we report the discovery of dBAZ2 and dBAZ2B, first-in-class Proteolysis Targeting Chimeras (PROTACs) degrading BAZ2A/B and BAZ2B, respectively. dBAZ2 induces BAZ2A/B degradation with a D_max ≥ 97% (BAZ2A_DC₅₀ = 180 nM; BAZ2B_DC₅₀ = 250 nM), while dBAZ2B selectively degrades BAZ2B with a DC₅₀ = 19 nM and D_max ≥ 97%. Degradation by dBAZ2 and dBAZ2B is almost complete within 2 h, is maintained for at least 3 days, and occurs in PC3 and MM1S cells, demonstrating the potential of these compounds as chemical probes to decipher the distinct biological functions of BAZ2A/B.

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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.