预约演示

更新于：2025-05-07

ASCL1

更新于：2025-05-07

基本信息

别名

achaete-scute family bHLH transcription factor 1、Achaete-scute homolog 1、ASCL1

+ [5]

简介

Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways. Directly binds the E box motif (5'-CANNTG-3') on promoters and promotes transcription of neuronal genes. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Plays a role at early stages of development of specific neural lineages in most regions of the CNS, and of several lineages in the PNS. Essential for the generation of olfactory and autonomic neurons. Acts synergistically with FOXN4 to specify the identity of V2b neurons rather than V2a from bipotential p2 progenitors during spinal cord neurogenesis, probably through DLL4-NOTCH signaling activation. Involved in the regulation of neuroendocrine cell development in the glandular stomach (By similarity).

关联

MYOCD/ASCL1基因疗法(Tenaya Therapeutics)

靶点

ASCL1 x MYOCD

作用机制

ASCL1 modulators [+1]

在研机构

Tenaya Therapeutics, Inc.

原研机构

Tenaya Therapeutics, Inc.

在研适应症

心脏病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

IDP-233

靶点

ASCL1

作用机制

ASCL1 inhibitors

在研机构

IDP Discovery Pharma SL

原研机构

IDP Discovery Pharma SL

在研适应症

小细胞肺癌 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ASCL1 相关的临床结果

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100 项与 ASCL1 相关的转化医学

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0 项与 ASCL1 相关的专利（医药）

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1,410

项与 ASCL1 相关的文献（医药）

2025-12-01·Molecular Biology Reports

Pharmacological inhibition of the Janus Kinases enhances ASCL1 protein stability and transcriptional activity

Article

作者: Veiga, Martina Koeva ; Presland, Jeremy ; Hanspal, Maya A ; Gillotin, Sébastien ; Shkura, Kirill

BACKGROUNDAchaete-Scute complex homolog 1 (ASCL1) is a multi-faceted pro-neural transcription factor, playing a role in several processes during embryonic development and into adulthood, including neural progenitor proliferation and neuronal differentiation. This versatility is achieved through tightly controlled expression of ASCL1, either via integrating intracellular signalling cues or stabilisation at the protein level. The role of kinases in ASCL1-mediated neurogenesis is emerging, but to date few kinases have been attributed to act directly or indirectly on ASCL1.METHODS AND RESULTSTo address this, we designed a cell-based high-throughput screen to identify kinase inhibitors that enhance ASCL1 protein levels. From this screen, two kinase inhibitors were identified to increase ASCL1 stability and transcriptional activity, and subsequent validation indicated that the effect was driven indirectly through Janus kinase family members.CONCLUSIONSThese compounds may serve as useful tools for further investigating the role played by kinases in regulating neurogenesis and ultimately enable better understanding of how ASCL1 integrates different signalling cues to orchestrate with high precision the differentiation of progenitor cells into neurons.

2025-07-01·Developmental Biology

ASCL1 protein domains with distinct functions in neuronal differentiation and subtype specification

Article

作者: Martinez, Madison J ; Nakada, Yuji ; Johnson, Jane E

ASCL1 is a neural basic helix-loop-helix (bHLH) transcription factor that plays essential roles during neural development, including neural differentiation and neuronal subtype specification. bHLH factors are defined by their motifs, including a basic region interacting with DNA and an HLH domain involved in protein-protein interactions. We previously defined specific regions within the bHLH domain of ASCL1 as important for its specific functions directing neuronal differentiation in the chick neural tube. Here, we build upon these findings to show how specific mutations within the basic region block DNA binding but not heterodimer formation with E-protein partners TCF3 (E12/E47) and TCF12 (HEB) yet have differential abilities to show dominant negative phenotypes. Additionally, truncating domains outside the bHLH define a nuclear localization signal, a requirement for the C-terminal acidic residues, and the non-essentiality of the N-terminal glutamine/alanine repeats. This structure/function analysis identifies functional domains for ASCL1 activity.

2025-06-01·Neural Regeneration Research

Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2

Article

作者: Wang, Yuchen ; He, Qing ; Chen, Gong ; Zhang, Kanghong ; Xu, Yuge ; Zhu, Mengjie ; Liang, Zhile ; Wang, Zhen

JOURNAL/nrgr/04.03/01300535-202506000-00030/figure1/v/2024-08-08T040853Z/r/image-tiff Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore, we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4 (astrocyte endfeet signal), CX43 (gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into pre-existing neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.

项与 ASCL1 相关的新闻（医药）

2025-04-18

·生物世界

Cancer Cell：何厚胜/秦骏团队揭示环状RNA在神经内分泌肿瘤中的关键作用

撰文丨王聪编辑丨王多鱼排版丨水成文环状 RNA（circRNA）是一类具有调控潜能的非编码 RNA，但其在前列腺癌和肺腺癌向神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）转化过程中的作用仍未得到探索。环状 RNA（circRNA）是一类主要通过反式剪接产生的非编码 RNA（ncRNA）。由于缺乏多聚腺苷酸（poly(A)）尾，circRNA 容易在 mRNA 测序中被遗漏，因此在许多转录组学分析研究中被忽略。目前，全转录组测序已报告了数千种具有组织和发育特异性表达模式的 circRNA。在癌症中，circRNA 主要通过与 miRNA 和蛋白质相互作用调节各种癌症特征，从而推动癌症进展。但 circRNA 在前列腺癌和肺腺癌向神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）转化过程中的作用仍未得到探索。2025 年 4 月 17 日，多伦多大学何厚胜教授团队联合中国科学院上海营养与健康研究所秦骏研究员团队，在 Cancer Cell 期刊发表了题为：Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation 的研究论文。该研究首次揭示了环状 RNA RMST（circRMST）在神经内分泌肿瘤转分化中的核心作用，阐明了其通过调控关键转录因子 SOX2 和 NKX2-1 稳定性的双重机制，为靶向肿瘤谱系可塑性提供了全新视角。癌细胞能够表现出谱系可塑性，即向另一种发育谱系转变的过程，以此作为逃避靶向治疗的一种机制。前列腺和肺是腺癌能够劫持神经元转录程序并转分化为侵袭性的神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）的两个部位。NEPC 和 SCLC 具有相似的基因组和转录组改变，包括几乎普遍存在的肿瘤抑制因子 RB1 和 TP53 的缺失以及神经元和发育转录因子的获得，这些可用于将肿瘤分类为分子亚型。在 SCLC 中，已提出四种亚型：SCLC-A（ASCL1）、SCLC-N（NEUROD1）、SCLC-P（POU2F3）和 SCLC-Y/I（YAP1/inflamed）。在 NEPC 中也观察到了类似的亚型，但其亚型分类尚未成为常规实践。尽管在神经内分泌转分化过程中已对许多蛋白因子进行了表征，但 circRNA 的作用在很大程度上仍未被探索，该研究旨在填补这一空白。在这项最新研究中，研究团队鉴定出环状 RNA——circRMST 是一种在神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）中异常丰富的 circRNA，且在人类和小鼠之间具有很强的保守性。利用 shRNA、siRNA、CRISPR-Cas13 和 CRISPR-Cas9 技术进行的功能研究一致表明，circRMST 对肿瘤生长以及神经内分泌命运主调控因子 ASCL1 的表达至关重要。在神经内分泌前列腺癌（NEPC）基因工程小鼠模型中，敲除 Rmst 基因可阻止神经内分泌转分化，使肿瘤维持在腺癌状态。从机制上来说，circRMST 与谱系转录因子 SOX2 和 NKX2-1 发生物理相互作用，一方面，circRMST 与 SOX2 直接结合，维持 SOX2 对 ASCL1 启动子的基因组结合能力；另一方面，circRMST 缺失会激活自噬-溶酶体途径，通过分子伴侣 HSC70 介导 NKX2-1 蛋白的降解。因此，circRMST 通过与 SOX2 和 NKX2-1 的双重作用来调控 ASCL1，其缺失会破坏神经内分泌转录网络的稳定性。该研究的核心发现：circRMST 在神经内分泌肿瘤中含量丰富且呈环状化；circRMST 对肿瘤生长和 ASCL1 表达至关重要；circRMST 对神经内分泌肿瘤的转分化是必需的；circRMST 通过与 SOX2 和 NKX2-1 相互作用并调节它们来调控 ASCL1。总的来说，这项研究研究强调了 circRMST 在驱动神经内分泌转分化以及维持神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）中的神经内分泌特征方面发挥着关键作用。其不仅可作为神经内分泌肿瘤的特异性标志物，更可能成为逆转肿瘤耐药性的新靶点。论文链接：https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00128-X设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群微信加群为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

信使RNA

2025-04-03

·GlobeNewswire-Health Care

Auron Presents New Preclinical Data for AUTX-703 in Small Cell Lung Cancer (SCLC)

AUTX-703, a novel and potent oral KAT2A and KAT2B protein degrader, inhibits growth and induces profound, persistent cell state differentiation in SCLC modelsNEWTON, Mass., April 03, 2025 (GLOBE NEWSWIRE) -- Auron Therapeutics, a clinical-stage biotechnology company targeting cell-state plasticity to improve patient outcomes in oncology and inflammatory disease, today announced data from a poster presentation at the 2025 Hot Topic in Basic and Translational Science: Small Cell Lung Cancer Meeting in New York, NY. The poster presented data from AUTX-703, a potent, selective and orally bioavailable heterobifunctional degrader of KAT2A/B, an AURIGIN-identified histone acetyltransferase driving small cell lung cancer (SCLC) and other tumor types. In a series of experiments, Auron showed that treatment with AUTX-703 potently degraded KAT2A/B, inhibited tumor growth, and induced durable cell state differentiation across models of SCLC. “We are excited to continue building on our findings highlighting AUTX-703’s potential as a novel, potent, small molecule degrader capable of inducing prolonged differentiation and inhibiting tumor growth in primary tumor models of SCLC ,” said Kate Yen, Ph.D., Founder and Chief Executive Officer of Auron. “Importantly, we have found that targeting the cell state driver, i.e. KAT2A, promotes differentiation and obstructs growth irrespective of the genomic mutation. With treatment extending out past 100 days we are pleased to see durable effects on cell state differentiation in solid tumors and look forward to advancing our Phase 1 trial in hematologic malignancies.” Specifically, the poster findings demonstrated: In SCLC cell lines, AUTX-703 treatment induces lasting effects, with prolonged treatment (over 100 days) driving a persistent epithelial transition and reduction in ASCL1 and L-MYC neuroendocrine markers.In SCLC patient-derived xenograft organoid (PDXO) models, AUTX-703 potently inhibits in vitro organoid and in vivo tumor growth and is well tolerated with oral dosing.In responding models, AUTX-703 decreases expression of MYC target genes.In models that undergo epithelial differentiation, AUTX-703 enhanced expression of antigen presentation genes, suggesting the potential to combine AUTX-703 with immune checkpoint inhibitors.In models that undergo neural differentiation, AUTX-703 enhanced DLL3 expression, suggesting the potential to combine AUTX-703 with tarlatamab. About Auron Therapeutics Auron Therapeutics is a platform-powered, product-driven company targeting cell-state plasticity to improve patient outcomes in oncology and inflammatory disease. Auron pioneered its AURIGIN™ platform, which uses AI and machine learning to compare cell states and identify novel drug targets, optimal development models, and biomarkers to facilitate proper patient selection, ultimately accelerating the development of effective and durable therapies. Using AURIGIN, the Company is building a pipeline of small molecule targeted therapies, led by a first-in-class, oral KAT2A/B degrader, AUTX-703, which is being developed for the treatment of both hematologic malignancies and solid tumors. For more information, please visit aurontx.com and follow us on LinkedIn. Investor Contact: Renee LeckTHRUST Strategic Communicationsrenee@thrustsc.com Media Contact: Carly ScadutoCarly Scaduto ConsultingCarly@carlyscadutoconsulting.com

临床1期

2025-02-22

·生物世界

Cancer Cell：复旦大学曹志伟/陈海泉团队绘制小细胞肺癌空间单细胞图谱，揭示其空间分子异质性及免疫互作生态位

编辑丨王多鱼排版丨水成文小细胞肺癌（small cell lung cancer， SCLC）的分子异质性已被揭示，但其在肿瘤免疫微环境中的空间组织和细胞间的相互作用仍有待阐明。 2025 年 2 月 20 日，复旦大学附属肿瘤医院陈海泉教授团队联合复旦大学生命科学学院曹志伟教授团队，在 Cancer Cell 期刊发表了题为：Integrative Spatial Analysis Reveals Tumor Heterogeneity and Immune Colony Niche Related to Clinical-outcomes in Small Cell Lung Cancer 的研究论文。该研究通过整合空间多组学（CODEX、CosMx）和传统组学技术，对 165 名小细胞肺癌（SCLC）患者的肿瘤样本进行了分析，系统性构建了小细胞肺癌空间单细胞图谱，揭示肿瘤内部高度分子异质性，并创新性开发了 ColonyMap 算法，深入解析了小细胞肺癌的免疫细胞空间互作规律，发现了可精准预测免疫疗效及患者预后的“MT2”细胞集落生态位。该研究的核心发现： 1、肿瘤异质性与分子亚型动态：多阳性肿瘤细胞（MPTC）：超过 10% 的肿瘤细胞共表达多个转录因子（如ASCL1+ NEUROD1+），尤其在 ASCL1 亚型（SCLC-A）中富集。这些细胞表现出高增殖（Ki67+）、上皮间质转化（Vimentin+）和 SLFN11 高表达，与较差的预后相关。分子亚型动态：SCLC-A 肿瘤中存在向 NEUROD1 和 YAP1 亚型过渡的轨迹，提示肿瘤表型可塑性可能与治疗抵抗相关。 2、空间微环境分析：细胞邻域（Cellular Neighborhoods，CNs）：通过 CODEX 技术识别了 20 种细胞邻域，其中 CN9（MPTC富集区）与 SLFN11 高表达、RBBP6 突变相关，预示侵袭性表型；而 CN17（ASCL1+ 肿瘤细胞富集区）与较好生存相关。免疫冷肿瘤特征：SCLC 整体免疫浸润水平低，但 YAP1 亚型（SCLC-Y）和 POU2F3 亚型（SCLC-P）分别表现出较高的巨噬细胞浸润和 Treg 细胞富集。 3、ColonyMap 算法与 MT2 免疫生态位： MT2 生态位：通过新开发的 ColonyMap 算法，发现由 M1 样巨噬细胞、CD8+ T 细胞和 NKT 细胞组成的空间聚集免疫生态位——MT2 生态位。MT2 高丰度患者的总生存期显著延长。免疫治疗预测价值：在独立免疫治疗队列中，MT2 生态位内 M1 样巨噬细胞比例高的患者对 PD-L1 抑制剂治疗的响应更佳。总的来说，该研究通过空间多组学揭示了非小细胞肺癌的肿瘤异质性和免疫微环境动态，提出了 MT2 生态位作为患者预后和免疫治疗响应的新标志，为小细胞肺癌的精准分型和治疗策略提供了重要依据。论文链接： https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00030-3 设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群微信加群为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

免疫疗法临床研究