Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

Kirberger Steven E.; Ycas Peter D.; Johnson Jorden A.; Chen Chen; Ciccone Michael F.; Woo Rinette W. L.; Urick Andrew K.; Zahid Huda; Shi Ke; Aihara Hideki; McAllister Sean D.; Kashani-Sabet Mohammed; Shi Junwei; Dickson Alex; dos Santos Camila O.; Pomerantz William C. K.

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Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

机译：BPTF溴结构域抑制剂的选择性，配体解构和细胞活性分析

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Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.

机译：含蛋白质转录因子（BPTF）的Bromodomain和PHD指是参与染色质重塑的表观遗传蛋白，并且是潜在的抗癌靶标。 BPTF溴结构域具有一种报道的小分子抑制剂（AU1，rac-1）。在这里，通过结合实验和分子动力学模拟，报道了导致活性对映体（S）-1的BPTF溴结构域配体的结构-活性关系取得的进展。另外，进行了配体解构分析以表征用于结合BPTF溴结构域的重要药效团。这些研究已经通过基于蛋白质的氟NMR方法得以实现，突出了该方法的选择性，配体解构和配体结合的多功能性。为了能够进一步分析生物学活性，使用CRISPR-Cas9和（S）-1在一组癌细胞系中进行了细胞生长分析，以识别对BPTF抑制敏感的基于细胞的模型系统。

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《Organic & biomolecular chemistry》 |2019年第7期|2020-2027|共8页
作者
Kirberger Steven E.; Ycas Peter D.; Johnson Jorden A.; Chen Chen; Ciccone Michael F.; Woo Rinette W. L.; Urick Andrew K.; Zahid Huda; Shi Ke; Aihara Hideki; McAllister Sean D.; Kashani-Sabet Mohammed; Shi Junwei; Dickson Alex; dos Santos Camila O.; Pomerantz William C. K.;
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Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA;

Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA;

Calif Pacific Med Ctr, Ctr Melanoma Res & Treatment, Res Inst, San Francisco, CA 94107 USA;

Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

Univ Minnesota Twin Cities, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA;

Univ Minnesota Twin Cities, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA;

Calif Pacific Med Ctr, Ctr Melanoma Res & Treatment, Res Inst, San Francisco, CA 94107 USA;

Calif Pacific Med Ctr, Ctr Melanoma Res & Treatment, Res Inst, San Francisco, CA 94107 USA;

Univ Penn, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48823 USA;

Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA;

Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA;

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2. Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis [J] . Myrianthopoulos Vassilios, Gaboriaud-Kolar Nicolas, Tallant Cynthia, Journal of Medicinal Chemistry . 2016,第19期

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4. ANALYSIS OF THE BROMODOMAIN BRD3 AND ITS INTERACTIONS WITH THE INHIBITOR JQ1 [C] . William B. Smith, Sean R. Marcsisin, Panagis Filippakopoulos, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2012

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5. Part One. Synthesis of optically active tryptophan derivatives with potential activity as indoleamine 2,3-dioxygenase inhibitors: An approach via asymmetric catalytic hydrogenation. Part Two. Design, synthesis and pharmacology of selective ligands for alpha1-containing GABA(A)/benzodiazepine receptor subtypes: SAR studies of beta-carbolines at positions -3 and -6 and their corresponding bivalent ligands. Part Three. First enantiospecific total synthesis of the important biogenetic intermediates, (+)-polyneuridine and (+)-polyneuridine aldehyde, as well as 16-epi-vellosimine and macusine A. [D] . Yin, Wenyuan. 2007

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6. BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands [O] . Kimberly Mayes, Zeinab Elsayed, Aiman Alhazmi, 2017

机译：BPTF抑制NK细胞活性和大量天然细胞毒性受体共配体
7. The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor [O] . -1

机译：新颖，弱溴和额外末端域（BET）溴域片段配体的优化至有效和选择性的第二溴琼瓜（BD2）抑制剂

Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

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