KAT6A is an enzyme that regulates biological processes that are linked to cancer cell proliferation and metastasis. Recent studies suggest that certain compounds from Withania somnifera may inhibit cancer growth by targeting KAT6A. However, the impact of mutations on KAT6A's structure and the inhibitory potential of compounds obtained from W. somnifera remain unclear. This study investigated three mutations, K181N, R242P and R325C, using molecular docking, molecular dynamics simulations and network pharmacology to assess their effects on KAT6A's interaction with its coenzyme, acetyl-CoA (CoA), and inhibitors (WM8014, withasomniferol B, withanolide E and sitoindoside IX). The results showed that R242P and R325C mutations significantly reduced binding affinity (from -12.94 kcal/mol to -9.96 and -7.00 kcal/mol, respectively) and increased RMSD values (from 1.860 to 2.296 and 2.373, respectively) compared to K181N (-11.86 kcal/mol and 1.698), suggesting altered enzyme activity. Notably, these mutations enhanced the inhibitory effects of the compounds from W. somnifera, particularly withanolide E, which showed reduced RMSD values (2.259-2.211, 2.045 and 1.985 for K181N, R242P, and R325C, respectively). Additionally, mutant complexes showed higher binding energies, including R325C-WM8014 (-90.53 kcal/mol), K181N-CoA (-90.50 kcal/mol) and R242P-withanolide E (-82.06 kcal/mol) compared to their corresponding wild-type complexes, which exhibited -85.25 kcal/mol, -69.30 kcal/mol and -57.08 kcal/mol, respectively. Network pharmacology also revealed that the compounds from Withania somnifera target KAT6A through multiple cancer pathways like PI3K-Akt signaling, apoptosis and chemical carcinogenesis. These findings suggest that specific KAT6A mutations may enhance the efficacy of the compounds from W. somnifera. However, further research is needed to validate these results, which could advance clinical applications and drug development for KAT6A-targeted cancer therapies.

2020-05-14·Journal of medicinal chemistry1区 · 医学

Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents

1区 · 医学

Article

作者: Cuellar, Matthew ; Mudududdla, Ramesh ; Strasser, Jessica M. ; Leaver, David J. ; Varghese, Swapna ; Monahan, Brendon J. ; Shackleford, David M. ; Priebbenow, Daniel L. ; Dahlin, Jayme L. ; Chung, Matthew C. ; Thomas, Tim ; Charman, Susan A. ; Mujumdar, Prashant ; Katneni, Kasiram ; Cleary, Benjamin ; Teguh, Silvia ; Parker, Michael W. ; Jousset Sabroux, Helene ; Huang, Fei ; Lagiakos, H. Rachel ; Voss, Anne K. ; White, Karen L. ; Baell, Jonathan B. ; Downer, Natalie L. ; Hermans, Stefan J. ; Nguyen, Nghi ; Sanchez, Julie ; Xue, Lian ; Sun, Yuxin ; Jarman, Kate E. ; Walters, Michael A. ; Falk, Hendrik ; Street, Ian P.

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC₅₀ of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC₅₀ = 6.3 nM; K_D = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

2019-08-08·Journal of medicinal chemistry1区 · 医学

Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

1区 · 医学

Article

作者: K. Katneni ; M. Cuellar ; S.A. Charman ; J.B. Baell ; L. Xue ; M. Chung ; S. Varghese ; D.L. Priebbenow ; P. Mujumdar ; S. Teguh ; I. Street ; D. Leaver ; J. Strasser ; H. Jousset Sabroux ; Walters ; H.R. Lagiakos ; M.W. Parker ; K.E. Jarman ; S. Hermans ; B. Monahan ; J. Dahlin ; J. Sanchez ; Y. Sun ; F. Huang ; H. Falk ; N.T. Nguyen ; R. Mudududdla ; B. Cleary ; K. White ; T. Thomas

A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC₅₀ of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC₅₀ = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.

项与 WM-8014 相关的新闻（医药）

2025-03-24

·精准药物

KAT6A抑制剂的研究进展

2024年，Nature medicine公布了KAT6A抑制剂PF-07248144在ER+/HER2-晚期乳腺癌患者中的单药治疗以及与fulvestrant联合治疗的Ⅰ期临床评估结果：安全性：单药治疗或联合用药导致的3级不良反应主要为：中性粒细胞减少、白细胞减少、贫血。单药组和联合治疗组分别只有1例和3例患者因此停药。有效性：单药治疗：客观缓解率: 11.4 %，中位缓解持续时间：12 months，中位无进展生存期：3.3 months；联合治疗：客观缓解率：30.2 %，中位缓解持续时间：9.2 months，中位无进展生存期：10.7 months。 PF-07248144在Ⅰ期临床结果发出的积极信号，这意味着KAT6A可能是乳腺癌治疗的重要靶点。 KAT6A简介赖氨酸乙酰转移酶6A（KAT6A，又称MOZ，MYST3）是MYST家族的一员，负责H3K23的乙酰化。MYST家族主要包含KAT6A、KAT6B、KAT7、KAT5、KAT8五位成员，它们具有共同的MYST催化结构域，其在氨基酸序列上具有95%的相似性。除MYST催化结构域外，KAT6A还主要包括NEMM结构域（负责核定位）、两个PHD锌指结构域（识别如H3K23me3组蛋白甲基化标记并介导蛋白相互作用）以及Glu/Asp富集区和Ser/Met富集区（主要负责转录激活）。KAT6A往往以四聚体复合物（KAT6A-BRPF1-ING5-EAF6）的形式发挥其底物识别以及乙酰化作用。(Nat Rev Drug Discov. 2025 Feb;24(2):112-133. /Trends Pharmacol Sci. 2024 Mar;45(3):243-254.) KAT6A与癌症 KAT6A在乳腺癌、卵巢癌、肺癌、宫颈癌和髓母细胞瘤等多种肿瘤中过表达。研究表明，KAT6A与CBP/NCOA3/EP300等发生染色体易位形成融合蛋白并驱动急性髓系白血病的发生发展；KAT6A的敲除能够诱导细胞周期停滞，抑制集落形成能力、促进细胞衰老，在小鼠体内显著抑制AML肿瘤生长，提高生存能力。（Cancer Discov (2022) 12 (3): 792-811.） KAT6A在15%的乳腺癌中发生扩增或过表达，其在ER+HER2-乳腺癌发生的频率更高。KAT6A高表达的肿瘤细胞中的ERα的mRNA和蛋白质水平更高，研究表明KAT6A结合在ESR1基因启动子近端区域催化H3发生乙酰化进而增强ERα的表达，当KAT6A的MYST结构域突变导致其催化活性丧失时KAT6A的表达不会对ERα的表达产生影响。在小鼠体内，KAT6A的敲除有效降低了ERα的表达并能显著抑制ER+HER2-乳腺癌肿瘤的生长，延长了小鼠的无进展生存期。（Oncogene. 2017 May 18;36(20):2910-2918. ）在肝癌细胞中，KAT6A的表达量显著高于正常细胞，并且对sorafenib耐药肝癌细胞中KAT6A的表达量也是显著提升的。KAT6A的敲除以及KAT6A抑制剂WM-1119与sorafenib联合使用能够有效抑制sorafenib耐药性肝癌细胞的生长。（British Journal of Cancer (2022) 127:202-210.） KAT6A抑制剂的研发进展（临床前） WM-8014：该化合物对KAT6A/6B的选择性较高，同时也保留了一定的KAT5/7的抑制活性。WM-8014能有效诱导细胞周期停止与细胞衰老，不会诱发细胞凋亡。但是WM-8014的血浆蛋白结合率高，不利于体内活性探究。（Nature. 2018 Aug;560(7717):253-257.） WM-1119：是在WM-8014的结构基础上优化得到的，在一定程度上提升了对KAT6A/6B的选择性以及抗增殖活性。只是该抑制剂的体内代谢降解速度较快，需要采用3-4次/天的给药频率。WM-1119在体内能够有效抑制淋巴瘤生长，耐受性良好。（Nature. 2018 Aug;560(7717):253-257.） CTx-648(PF-9363)：是一种KAT6A/6B的高选择性抑制剂，能够有效抑制H3K23的乙酰化，抗增殖活性强。在ER+HER2-乳腺癌肿瘤、PDX模型以及氟维斯群抗性的乳腺癌模型中CTx-648的抗肿瘤活性显著，有效提升了小鼠的生存能力。（Cell Chem Biol. 2023 Oct 19;30(10):1191-1210.e20. ） BAY-184: KAT6A/B的高效抑制剂，仍保留对KAT7抑制活性。BAY-184能够有效抑制多种ER阳性乳腺癌细胞的生长。代谢稳定性一般，半衰期短，口服生物利用度中等（60%）。BAY-184以口服给药的方式实现有效的肿瘤生长抑制活性耐受性良好。（J. Med. Chem. 2024, 67, 19282−19303.） KAT6A抑制剂的研发进展（临床评估） PF-07248144：由辉瑞公司研发，如开头所述在ER+/HER2-晚期乳腺癌患者中体现初步疗效。（NCT04606446） OP-3136: Olema公司研发的KAT6A选择性抑制剂，该抑制剂能够联合抗激素药物Fulvestrant、Palazestrant或者CDK4/6抑制剂Ribociclib在KAT6A过表达的ER阳性乳腺癌细胞中实现更有效的抗增殖活性，在T47D CDX模型中能够有效抑制肿瘤生长。（Olema官网）该抑制剂用于治疗晚期或转移性实体瘤，目前处于临床招募阶段（NCT06784193）。 MEN2312:由英矽智能开发的KAT6A选择性抑制剂，目前处于Ⅰ期临床招募阶段，单一或联合SERD抑制剂Elacestrant用于治疗晚期乳腺癌。（NCT06638307）声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床2期信使RNA临床结果

100 项与 WM-8014 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床前	澳大利亚	Monash University	2020-03-02
肝细胞癌	药物发现	中国	南京工业大学	2018-08-01
肝细胞癌	药物发现	澳大利亚	Monash University	2018-08-01
淋巴瘤	药物发现	中国	南京工业大学	2018-08-01
淋巴瘤	药物发现	澳大利亚	Monash University	2018-08-01