作者: Stott, Gordon M. ; Quaranta, Vito ; Liu, Qi ; Weissmiller, April M. ; Moore, William J. ; Meyer, Christian T. ; Grieb, Brian C. ; Savona, Michael R. ; Fesik, Stephen W. ; Howard, Gregory C. ; Tansey, William P. ; Silver, Alexander J. ; Lee, Taekyu ; Wang, Jing ; Smith, Brianna N. ; Lorey, Shelly L. ; Teuscher, Kevin B.

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the “WIN” site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild-type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood-borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood-borne cancers and forecast expanded utility of WINi against other cancer types.

2024-06-25·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes

Article

作者: Kuroda, Mitzi I. ; Cole, Philip A. ; Kang, Hyuckjoon ; Whedon, Samuel D. ; Smolko, Anne E. ; Olsen, Sarah Naomi ; Sullivan, Daniel W. ; Armstrong, Scott A. ; Baell, Jonathan B.

Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of acute myeloid leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Furthermore, transcription levels in MOZ-TIF2 cells positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of unique gene sets, and their cellular models exhibit distinct sensitivities to multiple small-molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate that these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.

2024-05-01·Cell reports. Medicine

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling

Article

作者: Zhang, Baogui ; Hao, Yujun ; Yan, Yugang ; Zhao, Rou ; Xiong, Huabao ; Tian, Dongxing ; Bie, Qingli ; Wang, Sen ; Zhao, Mingsheng ; Dong, Guanjun ; Zhang, Bin ; He, Baoyu ; Xu, Wenrong ; Zhang, Yanhua

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

项与 SNDX-50469 相关的新闻（医药）

2026-01-26

·拜尔迪生物

小分子化合物助力干细胞研究

干细胞，被誉为“生命的种子”，因其强大的自我更新与分化能力，成为再生医学的核心希望。全球最具影响力的科技智库之一《MIT Technology Review》在其2025年“十大突破性技术”（10 Breakthrough Technologies）评选出的10大可能引领未来的重大进展中，“有效的干细胞疗法”首次入选，并被评为干细胞治愈疾病的新希望。化学小分子：更安全的“基因替代者” 小分子化合物通过调控细胞信号通路和表观遗传修饰，规避基因操作风险，成为重编程新技术焦点。核心优势： 1、无需基因插入：避免致癌突变风险 2、操作简便：化合物组合精准调控细胞状态 3、可逆性强：浓度调整灵活终止作用产品推荐滑动查看全部产品点击产品名查看产品详情产品名/货号规格/纯度DZNepA7415021mg (纯度≥99%) E-616452A1586471mg（纯度≥99%） CHIR99021A1330521mg（纯度≥99%） TTNPB A7009491mg（纯度≥98%） 5-azacytidineA38683710mg（纯度≥99%） PD0325901 A3704825mg（纯度≥98%） 17-AAG A2204625mg（纯度≥98%） HS1A A3277512mg（纯度≥99%） BIO A5388181mg（纯度≥99%） valproic acid A14379425mg（纯度≥99%） Forskolin A2261931mg（纯度≥98%） BrdU A38694225mg（纯度≥99%） Vitamin C A18282110mg（纯度≥99%） AM580 A1848901mg（纯度≥98%） EPZ5676 A2282481mg（纯度≥98%） SGC0946 A7025741mg（纯度≥99%） Y27632A1123581mg（纯度≥99%） ABT869A1475741mg（纯度≥99%） JNKIN8A2063532mg（纯度≥98%） EPZ004777A1626901mg（纯度≥99%） UNC0379A2117081mg（纯度≥98%） SB590885A7209771mg（纯度≥98%） IWP2A2509535mg（纯度≥99%） VTP50469A13649951mg（纯度≥98%） CX4945A1037482mg（纯度≥99%） Tranylcypromine A11607010mg（纯度≥99%） 5-iodotubercidin A177991 3mg（纯度≥98%） 1-Azakenpaullone A192559 2mg（纯度≥98%）传统干细胞技术困境自1998年人类胚胎干细胞（hESCs）首次成功分离以来，其无限自我更新和多向分化潜能引发了再生医学的革命性期待[1]。然而，hESCs依赖胚胎破坏的特性引发了激烈的伦理争议，尤其在宗教和生命伦理学界，围绕“胚胎人格”的辩论促使多国立法限制相关研究（如美国2001年联邦经费禁令）。这一伦理困境推动了2006年诱导多能干细胞（iPSCs）技术的突破。 2006年，Takahashi等筛选到了Oct4、Sox2、c-Myc和Klf4四个在小鼠胚胎发育早期高表达的转录因子，利用逆转录病毒将其导入分化成熟的皮肤成纤维细胞中（OSKM四因子诱导），得到具有自我更新能力和分化潜能的细胞，并命名为诱导多能干细胞[2]。但由于OSKM四因子诱导多能干细胞技术需要病毒介导，并转入原癌基因c-Myc和Klf4，存在致癌和插入突变风险。2008年，《Cell Research》综述指出，OSKM过表达重编程的本质是激活特定信号通路，化合物小分子通过取代基因导入诱导体细胞重编程为多能干细胞具有可行性[3]。2009年，转化生长因子-β（TGF-β）信号通路抑制剂被发现可替代Sox2和c-Myc诱导小鼠成纤维细胞重编程为多能干细胞，由此开启化学小分子诱导多能干干细胞的探索[4]。小分子化合物维持干细胞干性小分子化合物可维持体外培养胚胎干细胞的干性与自我更新能力。在经典2i/L培养基中添加GSK-3抑制剂CHIR99021和MEK1抑制剂PD0325901，可稳定胚胎干细胞的干性并促进其分化为不同胚层细胞[5]。研究发现，添加小分子Stemazole可显著抑制人胚胎干细胞凋亡，促增殖并维持分化潜能[6]。HSP90抑制剂17-AAG和HSF1激活剂可激活HSF1，促进体外造血干细胞稳态维持，抑制衰老[7]。GSK-3抑制剂BIO（GSK 3 Inhibitor IX ）则能抑制牙髓干细胞（hDPSCs）凋亡，促进碱性磷酸酶（ALP）表达，维持多能性[8]。突破性研究结果一、小分子化合物诱导小鼠多能干细胞使用Valproic acid（VPA)、TGFBR1抑制剂RepSox（E-616452 、CHIR99021、和单胺氧化酶抑制剂Tranylcypromine的V6CT组合联合Oct4，可将小鼠皮肤成纤维细胞高效重编程为多能干细胞。此类iPSCs具备干细胞样形态、高碱性磷酸酶活性及胚胎干细胞特征的基因表达谱（Sox2、Nanog等），去甲基化水平和基因表达谱与胚胎干细胞类似，且可形成畸胎瘤[9]。2013年进一步优化VC6T组合，加入Forskolin、TTNPB和EZH2抑制剂DZNep (3-Deazaneplanocin A)，成功诱导CiPSCs（化学诱导多能干细胞），后简化为CHIR99021、RepSox、Forskolin和DZNep 组合[10]。但该方案诱导周期长达40天，效率仅0.2%，难以匹敌OSKM四因子法。2015年，BrdU替代Oct4的突破实现小鼠胚胎成纤维细胞高效重编程。BrdU、CHIR99021、TTNPB和Forskolin的药物组合在先前报道的小分子化合物诱导人多能干细胞方案基础上，开创性地加入经典的表征细胞增殖状态的BrdU改造细胞的染色质状态[11]。2018年Cao等报道了新化合物组合含Vitamin C、BMP4、TTNPB、BrdU、VPA、Forskolin、RAR激动剂AM580、DOT1样组氨酸甲基转移酶 (DOT1 like histone lysinemethyltransferase，DOT1L)抑制剂EPZ5676与SGC0946和DZNep成功将小鼠胚胎成纤维细胞和肺成纤维细胞重编程诱导为多能干细胞[11]，该小分子化合物组合在先前基础上引入另一个表观遗传修饰因子DOT1L的抑制剂，大幅缩短了化学诱导多能干细胞的时间。二、小分子化合物诱导人多能干细胞在人类体细胞中实现化合物小分子重编程才是化学重编程走向应用的关键，小分子化合物诱导人多能干细胞的体系和流程更加复杂，研究利用不同的小分子组合通过不同阶段的分阶段诱导最终产生具有自我更新能力和多分化潜能的人诱导多能干细胞。人源体细胞重编程需分阶段诱导[12]： Step1——上皮样细胞诱导：CHIR99021、RepSox、TTNPB、Y27632、ABT869（Linifanib）、SAG Step2——去分化为可塑性细胞：JNKIN8、5-氮杂胞苷、tranylcypromine Step3——高表达Oct4的XEN样细胞诱导：VPA、DZNep、EPZ004777、UNC037等 Step4——终末重编程为多能干细胞：CHIR99021、SB590885、IWP2等优化版化合物方案在实现小分子化合物组合诱导人体细胞向多能干细胞的重编程之后，2023年一项研究报道了一个更加高效的诱导人多能干细胞的化合物组合方案[13]。诱导时间缩至20天，效率提升至8.75%。在诱导的第一阶段加入JNKIN8、MEN1抑制剂VTP50469和AKT激酶抑制剂提高了第一阶段上皮样细胞的诱导效率；在诱导的第二阶段加入EPZ5676和DZNep可直接跳过XEN样细胞阶段将细胞重编程为多能干细胞，从而将诱导时间从60天缩短至20天。此外，在此基础上加入VTP50469、AKT激酶抑制剂、酪蛋白激酶2(casein kinase 2，CK2)抑制剂CX4945和胞苷激酶抑制剂5-iodotubercidin。该研究发现JNKIN8对重编程不可或缺，JNKIN8的缺失导致多能干细胞凋亡凋亡率上升。化学诱导全能干细胞多能干细胞无法分化为胚外组织或形成胚胎，而小分子药物可突破此限制。2022年，PD0325901（Mirdametinib 、IWR1、TSA等组合将人胚胎干细胞重编程为具有胚胎形成能力的全能干细胞[14]。2023年，TTNPB、1-Azakenpaullone和WS6组合诱导小鼠多能性干细胞至类2细胞阶段全能干细胞[15]。就安全性而言，化学诱导多能干细胞与传统的OSKM诱导多能干细胞相比，化学诱导多能干细胞的基因组稳定性更高，其在电离辐射后突变更少，且损伤修复能力更强。虽然小分子化合物诱导多能干细胞的效率远低于传统的OSKM诱导方法，但是，其优越的安全性和高度的可操纵性仍然使其成为再生医学中的希望之一。结语化学小分子以“细胞魔法师”之姿重塑再生医学边界，从实验室迈向临床，静默技术革命正改写器官修复与疾病治疗未来。关注《Cell Stem Cell》《Nature》等期刊报道，与AmBeed共同见证生命科学新纪元！参考文献 1.Thomson, J.A., et al., Embryonic stem cell lines drived from human blastocysts. Science, 1998. 282(5391): p.1145-7. 2.Takahashi, K. and S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126(4): p.663-676. 3.Pei, D., The magic continues for the iPS strategy. Cell Res, 2008. 18(2): p.221-3. 4.Ichida, J.K., et al., A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 2009. 5(5): p.491-503. 5.Sim, Y.J., et al., 2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms. Stem Cell Reports, 2017. 8(5): p.1312-1328. 6.Sun, Y., et al., Stemazole promotes survival and preserves stemness in human embryonic stem cells. Febs j, 2018. 285(3): p.531-541. 7.Kruta, M., et al., Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging. Cell Stem Cell, 2021. 28(11): p.1950-1965.e6. 8.Kornsuthisopon, C., et al., 6-Bromoindirubin-3'-Oxime Regulates Colony Formation, Apoptosis, and Odonto/Osteogenic Differentiation in Human Dental Pulp Stem Cells. Int J Mol Sci, 2022. 23(15). 9.Li, Y., et al., Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res, 2011. 21(1): p.196-204. 10.Hou, P., et al., Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 2013. 341(6146): p.651-4. 11.Cao, S., et al., Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency. Cell Stem Cell, 2018. 22(4): p.529-542.e5. 12.Guan, J., et al., Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature, 2022. 605(7909): p.325-331. 13.Liuyang, S., et al., Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming. Cell Stem Cell, 2023. 30(4): p.450-459.e9. 14.Mazid, M.A., et al., Rolling back human pluripotent stem cells to an eight-cell embryo-like stage. Nature, 2022. 605(7909): p.315-324. 15.Hu, Y., et al., Induction of mouse totipotent stem cells by a defined chemical cocktail. Nature, 2023. 617(7962): p.792-797. 北京拜尔迪生物是Ambeed的授权代理商，更多产品，欢迎咨询订购！北京拜尔迪热线：010-62960866 网址：www.biodee.net 北京拜尔迪生物(BioDee)，成立于2003年，国家级高新技术企业，多个进口品牌和优秀国产品牌的一级代理商，专注于生命科学领域，为客户提供试剂、耗材、仪器等产品，涵盖了细胞生物学、微生物学、植物学、分子生物学、生物化学、免疫学等领域。

临床1期临床结果细胞疗法

100 项与 SNDX-50469 相关的药物交易

登录后查看更多信息