BRPF1

关注并星标CPHI制药在线 赖氨酸乙酰转移酶（KAT）是一类能够催化乙酰基从乙酰辅酶A上转移到蛋白质底物赖氨酸ε-氨基上的酶，可以乙酰化组蛋白、HMG（高迁移率组）蛋白、转录因子和核受体等多种蛋白质的多个赖氨酸位点，其中组蛋白乙酰化是最典型的。因此，赖氨酸乙酰转移酶（KATs）通常被称为组蛋白乙酰转移酶（HATs）。 赖氨酸乙酰化是一种可逆的、动态的翻译后修饰过程，由KATs和去乙酰化酶(KDATs)共同调节，它是最常见的蛋白质翻译后修饰（PTM）之一，影响数百种蛋白质，并调节许多重要的生物过程。 根据蛋白序列和结构同源性的不同，KATs主要分为4个不同的家族，即GNAT/PCAF（GCN5）家族、p300/CBP家族、MYST家族和SRC/ACTF家族。其中MYST蛋白家族最复杂，包括MOZ（KAT6A）、MOF（KAT8）、MORF（KAT6B）、TIP60（KAT5）和HBO1（KAT7）五个成员。MYST家族成员都含有高度保守的“MYST”结构域，其通常由HAT结构域、C2HC锌指结构域和乙酰辅酶A结合位点组成。 关于KAT6A KAT6A，又称MYST3，是2004个氨基酸长的蛋白质，由一个双PHD锌指结构域、一个N端MYST结构域以及一个富含谷氨酸/天冬氨酸的区域和C端有富含丝氨酸/蛋氨酸的区域组成。 KAT6A及其类似物KAT6B通过MYST结构域与BRPF1/2/3相互作用，后者介导与ING5(或类似物ING4)及MYST/ MEAF6的相互作用，形成四聚体复合体。该复合体的BRPF1和ING4/5亚基也是组蛋白修饰的读本，可以乙酰化组蛋白H3尾部的赖氨酸残基。组蛋白赖氨酸残基H3K9和H3K23乙酰化需要KAT6A组蛋白乙酰转移酶(HAT)，而在体内正常的H3K23乙酰化需要KAT6B，这些组蛋白修饰过程均与转录活性基因相关。 KAT6A在大脑、心脏、肝脏、皮肤等组织中表达，在分裂活跃的细胞中尤其丰富，如干细胞和癌细胞。研究发现，KAT6A基因的突变与许多发育障碍有关，如鲁宾斯坦-泰必氏综合症和史密斯-马杰尼斯综合征。而且，KAT6A在多种类型的癌症中被发现表达失调或异常，如乳腺癌、肺癌、卵巢癌的扩增，以及急性髓系白血病（AML）中的致癌融合。 KAT6A在肿瘤进展的分子机制目前还不清楚。当前一些研究发现，在雌激素受体阳性（ER+）、KAT6A过表达的乳腺癌中，KAT6A通过与其启动子结合来调节ERα的表达。在前列腺癌和舌鳞癌细胞中，KAT6B通过调节PI3K和AKT信号通路来促进肿瘤细胞增殖。 此外，研究还发现KAT6A是CD4+ T细胞体外增殖和Th1/Th17分化所必需的，其通过在CD4+ T细胞核内调节乙酰化蛋白（H3K9ac和H3K27ac）水平，维持多个糖酵解基因启动子区域的乙酰化状态，抑制KAT6A可抑制自身免疫中CD4+ T 细胞的效应功能。这意味着KAT6A有望成为治疗自免疾病的潜在靶点。 KAT6A抑制剂进展 随着对KAT6A研究的深入，已有药企开始关注KAT6A靶点，并研发出相关药物，如PF-07248144和ISM5043。其中PF-07248144进展最快，已进入1期临床。 PF-07248144是辉瑞与Oncology One联合开发的一款选择性、口服KAT6A/KAT6B抑制剂，被开发单药，或联合内分泌治疗（氟维司群或来曲唑）、CDK4/6抑制剂palbociclib或CDK4抑制剂PF-07220060治疗晚期或转移性实体瘤。 2024 ASCO上公布的1期临床试验结果显示：PF-07248144单药或联合氟维司群在CDK4/6抑制剂治疗进展的ER+/HER2-晚期乳腺癌中展现出良好的疗效。具体数据为：PF-07248144单药治疗的ORR为11.4%，DoR为12.0个月，CBR为31.4%，中位PFS为3.3个月；PF-07248144+氟维司群治疗组整体的ORR为30.2%，中位DoR为9.2个月，研究者评估的患者中位PFS为10.7个月，远远超过此前临床研究中CDK4/6抑制剂经治患者后线使用氟维司群或其它治疗方案的中位PFS（一般仅为1-2个月）。而且，基于ctDNA检测基因突变状态的分析显示，PF-07248144+氟维司群联合疗法的效果并不受患者ESR1及PIK3CA/PTEN/AKT1基因突变状态的影响，且联合疗法能显著降低ESR1变异等位基因分数（VAF）水平。 安全性方面，PF-07248144表现良好，最常见的TRAEs主要是味觉障碍、中性粒细胞减少和贫血。试验中，三级及以上TRAEs的发生率较高，其中单药组为54.3%，联合治疗组为62.8%，但单药组和联合治疗组分别只有1例和3例患者因此停药。 ISM5043是由英矽智能人工智能平台Pharma.AI辅助设计和开发的小分子抑制剂，旨在抑制KAT6活性，并在转录水平阻断ERα表达，使其有潜力克服因ESR1突变带来的内分泌疗法耐药问题。临床前研究显示：ISM5043在多个细胞系移植瘤模型（CDX）和人源异种移植模型（PDX）中均显示出对KAT6A的强效抑制作用，表现出良好的疗效和安全性。 2024年1月，美纳里尼全资子公司Stemline Therapeutics与英矽智能达成一项授权许可协议，获得后者KAT6靶向新型小分子抑制剂ISM5043的全球独家开发和商业化权益，交易总金额预计可能超过5亿美元。 Stemline Therapeutics引进ISM5043是为了加强ER+、HER-乳腺癌领域的布局，其开发的SERD艾拉司群已经获批上市。ISM5043有望成为艾拉司群治疗乳腺癌的最佳搭档。 总结 KAT6A是肿瘤药研发领域的新靶点，目前相关药物较少。在研药物中辉瑞的PF-07248144进展最快，1期临床已取得积极结果。我国药企英矽智能在KAT6A抑制剂领域也有布局，其开发的ISM5043已顺利出海。当前，KAT6A抑制剂适应症主要针对ER+乳腺癌等实体瘤。但随着对KAT6A研究的深入，发现KAT6A也有望成为自免疾病药物研发的潜力靶点。 END 【智药研习社抗体系列直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

BRD4, a member of the bromodomain and extra-terminal (BET) protein family, plays a crucial role in the regulation of gene expression and chromatin remodeling in the human body. It acts as an epigenetic reader, recognizing and binding to acetylated lysine residues on histone proteins, thereby facilitating the recruitment of transcriptional machinery to specific gene loci. BRD4's involvement in various cellular processes, including cell cycle progression, inflammation, and cancer, makes it an attractive target for therapeutic intervention. Inhibitors targeting BRD4 have shown promising results in preclinical and clinical studies, highlighting its potential as a therapeutic target for various diseases. With the advancement of technology, researchers have developed a variety of BRD4 inhibitors through computer-assisted drug design, which work by targeting and inhibiting the BRD4 domain, inducing apoptosis in tumor cells, and thereby achieving anti-tumor effects. To date, reported small molecule inhibitors targeting BRD4 mainly include azole class (IBET151), purine class, quinone class and its derivatives (RVX-208), tetrahydroquinoline class (IBET726), and naphthylamine class, etc. Among these, JQ1 was the first publicly disclosed BET inhibitor, which achieves cell differentiation and apoptosis by competitively binding with the BRD4 fusion oncogene (BRD4-NUT), causing BRD4-NUT to dissociate from chromatin. However, JQ1 has a short half-life and increasing the dosage to maintain its effectiveness also increases the drug's side effects. Subsequent researchers addressed this drawback by structurally modifying JQ1, resulting in small molecular compounds like OTX015, MS417, CPI203, etc. BET proteins are widely expressed in human tissues, participate in the regulation of gene transcription, influence cell cycle processes, and abnormal expression of BRD4 can lead to the occurrence of various diseases such as tumors, cardiovascular diseases, inflammation, etc. In recent years, drug research targeting BRD4 has received widespread attention, and monotherapy or combined therapy targeting the BET family has shown promising clinical results. However, most of the current inhibitors are non-selective with poor specificity. Therefore, there is a new direction in research to find new BET inhibitors with better selectivity and higher specificity. How do they work?From a biomedical perspective, BRD4 inhibitors are a type of drug that target and inhibit the activity of the BRD4 protein. BRD4 is a member of the bromodomain and extraterminal (BET) protein family, which plays a crucial role in regulating gene expression. By inhibiting BRD4, these inhibitors can interfere with the binding of BRD4 to chromatin, leading to the suppression of specific genes involved in various cellular processes. BRD4 inhibitors have gained significant attention in the field of cancer research, particularly in the development of targeted therapies. Cancer cells often rely on certain genes for their survival and proliferation, and BRD4 inhibitors can disrupt the expression of these genes, potentially leading to the inhibition of tumor growth. Additionally, BRD4 inhibitors have shown promise in other disease areas, such as inflammation and cardiovascular disorders. It's important to note that BRD4 inhibitors are still under investigation and clinical trials to determine their efficacy and safety profiles. List of BRD4 InhibitorsThe currently marketed BRD4 inhibitors include: ApabetaloneBirabresib dihydrateNHWD-870PLX-2853AZD-5153PLX-51107RNK05047ABBV-744ACC-010CK-103For more information, please click on the image below. What are BRD4 inhibitors used for?BRD4 inhibitors have shown promise in other disease areas, such as inflammation and cardiovascular disorders. For more information, please click on the image below to log in and search. How to obtain the latest development progress of BRD4 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of BRD4 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!