Polybromo-1 Bromodomain Inhibitor Selectivity Is Mediated by a Unique Ligand-Binding Pocket

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-09-16 DOI:10.1021/acsmedchemlett.5c00352

Raymundo Nuñez, , , Karina L. Bursch, , , Savannah J. Makowski, , , Mingguang Xue, , , Kira A. Cozzolino, , , Shifali Shishodia, , , Robert F. Keyes, , , Nan Zhu, , and , Brian C. Smith*,

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Abstract

Polybromo-1 (PBRM1) is a key subunit of the PBAF chromatin remodeling complex, linking histone lysine acetylation to transcriptional regulation through six tandem bromodomains. Targeting PBRM1 bromodomains offers therapeutic potential in prostate cancer and clear cell renal cell carcinoma. Most existing PBRM1 inhibitors also bind the structurally related SMARCA2/4 bromodomains and lack target selectivity. We and others recently developed selective PBRM1 bromodomain inhibitors that do not bind the SMARCA2/4 bromodomains. However, the key residues and binding interactions leading to selectivity for PBRM1 were unknown. Here, we solved an X-ray crystal structure of PBRM1-BD2 bound to our selective PBRM1 bromodomain inhibitor (PB16). Through mutagenesis, we identify a unique tyrosine residue in PBRM1 that creates a distinct binding pocket essential for selective inhibitor binding. Unlike GNE-235, another selective PBRM1 bromodomain inhibitor, PB16 demonstrates cell activity in PBRM1-dependent cancer models, making it a promising lead candidate to further develop for targeted cancer therapy.

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一个独特的配体结合口袋介导了多溴-1溴结构域抑制剂的选择性

多溴-1 （PBRM1）是PBAF染色质重塑复合体的关键亚基，通过6个串联溴结构域将组蛋白赖氨酸乙酰化与转录调控联系起来。靶向PBRM1溴结构域在前列腺癌和透明细胞肾细胞癌中具有治疗潜力。大多数现有的PBRM1抑制剂也结合结构相关的SMARCA2/4溴结构域，缺乏靶向选择性。我们和其他人最近开发了不结合SMARCA2/4溴结构域的选择性PBRM1溴结构域抑制剂。然而，导致PBRM1选择性的关键残基和结合相互作用尚不清楚。在这里，我们解决了PBRM1- bd2结合我们的选择性PBRM1溴域抑制剂（PB16）的x射线晶体结构。通过诱变，我们在PBRM1中发现了一个独特的酪氨酸残基，该残基为选择性抑制剂的结合创造了一个独特的结合口袋。与另一种选择性PBRM1溴结构域抑制剂GNE-235不同，PB16在PBRM1依赖的癌症模型中显示出细胞活性，使其成为进一步开发靶向癌症治疗的有希望的主要候选药物。

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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.