A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

开始日期2025-03-20

申办/合作机构

City of Hope National Medical Center

[+1]

NCT06284460 / Withdrawn临床1/2期IIT

Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ASTX029 that can be given in combination with ASTX727 to participants who have RAS-mutant MDS or MDS/MPN. The goal of Part 2 of this clinical research study is to learn if the dose of ASTX029 found in Part 1 can help to control the disease when used in combination with ASTX727.

开始日期2025-01-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06575725 / Not yet recruiting临床2期IIT

A Phase 2 Study of Botensilimab, Balstilimab and Regorafenib in Patients With Microsatellite Stable Colorectal Cancer

This phase II trial studies how well the combination of botensilimab, balstilimab and regorafenib works compared to botensilimab and balstilimab in treating patients with microsatellite stable colorectal cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps to slow or stop the spread of tumor cells. The combination of botensilimab, balstilimab and regorafenib or botensilimab and balstilimab may be a safe and effective treatment for advanced or metastatic microsatellite stable colorectal cancer.

开始日期2024-11-01

申办/合作机构

Hope Medical Center

[+1]

100 项与 MAPK 相关的临床结果

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100 项与 MAPK 相关的转化医学

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0 项与 MAPK 相关的专利（医药）

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163,914

项与 MAPK 相关的文献（医药）

2025-08-01·Neural Regeneration Research

AAV2-PDE6B restores retinal structure and function in the retinal degeneration 10 mouse model of retinitis pigmentosa by promoting phototransduction and inhibiting apoptosis

Article

作者: Zhang, Xiaoli ; Han, Jinfeng ; Liu, Jingyang ; Lei, Bo ; Wang, Weiping ; Qiu, Ruiqi ; Jin, Xiuxiu ; Yang, Mingzhu

JOURNAL/nrgr/04.03/01300535-202508000-00030/figure1/v/2024-09-30T120553Z/r/image-tiff Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death. However, there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation. Adeno-associated virus (AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa. The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function. To do this, we injected retinal degeneration 10 (rd10) mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark- and light-adapted electroretinogram, optical coherence tomography, and immunofluorescence. Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment, and the results from this analysis were verified by real-time polymerase chain reaction and western blotting. AAV2-PDE6B injection significantly upregulated PDE6β expression, preserved electroretinogram responses, and preserved outer nuclear layer thickness in rd10 mice. Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception, and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice. Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways. Furthermore, the phototransduction-related proteins Pde6α, Rom1, Rho, Aldh1a1, and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment. Finally, Bax/Bcl-2, p-ERK/ERK, and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment. Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.

2025-06-01·Neural Regeneration Research

Enhancing m6A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Article

作者: Qin, Tian ; Lu, Hongbin ; Cao, Yong ; Qin, Yiming ; Hu, Jianzhong ; Li, Chengjun ; Jin, Yuxin ; Yuan, Feifei

JOURNAL/nrgr/04.03/01300535-202506000-00026/figure1/v/2024-08-08T040853Z/r/image-tiff Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine (m6A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m6A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m6A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m6A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m6A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

2025-04-01·Neural Regeneration Research

Hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect neurons from cardiac arrest–induced pyroptosis

Article

作者: Huang, Hanlin ; Gong, Zheng ; Tang, Xiahong ; Wang, Yu ; Ke, Jun ; Chen, Feng ; Lin, Qingming ; Wu, Jiali ; Zhuang, Yangping ; Zheng, Nan ; You, Yan

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

1,323

项与 MAPK 相关的新闻（医药）

2024-10-31

·乐威医药

探索分子砌块：氧（氮）杂环丁烷磺酰氟

在药物研发的领域中，科学家们一直在探索新的分子结构和化学合成方法，以寻找更有效、更安全的药物。今天要给大家介绍的是一项来自伦敦帝国理工学院和辉瑞研发中心的研究，他们发现的「氧杂环丁烷和氮杂环丁烷磺酰氟」在药物发现中的巨大潜力。有感兴趣的朋友，点击“在看”与“转发”后，联系公众号助理索取原文！小分子杂环：药物设计的新宠 1.小分子杂环：药物设计的新宠在药物化学中，精确控制分子的性质和构象是至关重要的。小分子极性基团，如氧杂环丁烷和氮杂环丁烷，因其独特的空间电子性质，成为了备受瞩目的生物电子等排体。它们可以模拟更常见官能团的性质，通过调整极性和氢键特性来增强药物与靶点的结合能力，同时还能影响药物的代谢稳定性、溶解度、吸收、分布和 pKa 值。目前，已经有一些含有氧杂环丁烷的化合物进入了临床试验阶段，氮杂环丁烷在已批准的药物中也逐渐崭露头角。多样的反应路径，丰富的化学结构 Defluorosulfonylative（deFS）耦合反应 OSF 和 ASF 试剂通过 deFS 反应途径，生成的碳正离子中间体可与多种亲核试剂耦合，从而合成了一系列新颖的化学结构。研究人员利用这一反应，合成了 11 种药物类似物，包括一些具有重要生物活性的分子，如治疗糖尿病诱导的免疫功能障碍的 SERCA 激活剂类似物，以及 MAPK14 抑制剂类似物等。 Sulfur–Fluoride Exchange（SuFEx）反应在阴离子条件下，OSF 试剂还能通过 SuFEx 途径生成氧杂环丁烷 - 硫（VI）衍生物。通过调整溶剂和亲核试剂的强度，研究人员成功解锁了这一反应路径，为药物分子的设计提供了更多的选择。合并药效团，创造新的药物设计元素研究人员还探索了将氧杂环丁烷与其他极性官能团合并的可能性。例如，通过 deFS 反应将氧杂环丁烷与 NH - 唑、亚砜亚胺和含磷官能团等结合，形成了多种新颖的化学结构，这些结构可能作为有价值的新型生物电子等排体或替代基团，为药物化学家提供了新的设计思路。含磷官能团作为药物化学结构单元尚未得到充分研究。膦酸酯和磷酸酯基团已被用于前药中以促进细胞膜通透性，而氧化膦在布加替尼获批后才开始受到更广泛的研究。人们越来越关注将这些结构单元引入类药分子中以调节 LogD 和溶解度。我们假设可以利用亚磷酸烷基酯试剂来捕获氧杂环丁烷碳正离子并提供相应的磷酸化氧杂环丁烷产物。含有氧杂环丁烷的新型结构基元可进行进一步衍生化（方案 2d）。氧杂环丁烷叠氮化物59经铜催化的叠氮-炔烃环加成反应（CuAAC）生成三唑88，拓展了氧杂环丁烷 1,2,3 - 三唑的潜在应用范围。氮杂环丁烷磺酰氟的独特魅力首次报道的 ASF 试剂与 OSF 试剂具有相似的反应性。它可以通过 deFS 反应合成3-芳基-3-取代的氮杂环丁烷衍生物，并且与多种亲核试剂具有良好的兼容性，包括一些复杂的晚期示例，如氟西汀和氨氯地平的氮杂环丁烷功能化衍生物。此外，ASF 试剂还能通过 SuFEx 反应与醇盐反应，展示了其与复杂分子共轭的潜力。在药物发现中的实际应用 PROTAC 连接子和分子胶设计在靶向蛋白质降解这一新兴领域中，OSF 和 ASF试剂展现出了独特的应用价值。研究人员利用这些试剂引入了cereblon-结合基序，为PROTAC连接子和分子胶提供了新的设计思路。这些新的设计可能改善其物理化学性质或溶解度特性，从而提高药物的疗效。靶蛋白的降解通过与 pomalidomide等E3连接酶配体的耦合反应，OSF和ASF试剂生成了新的降解剂基序，展示了它们在靶向蛋白质降解领域的应用潜力。这为开发新的药物治疗方法提供了新的途径。结论与展望这项研究展示了OSF和ASF 试剂在药物发现中的强大潜力。它们不仅可以通过多种反应路径合成具有新颖结构的化合物，还能为药物分子的设计提供新的思路和方法。未来，我们期待这些试剂能够在药物研发中得到更广泛的应用，为人类健康带来更多的福祉。版权声明：本文内容及图片，如有侵权请联系删除。免责声明：本文内容仅作信息交流学习，并不反映任何意见及观点。往期推荐乐威医药（欧洲）分公司正式成立乐威医药沧州GMP生产基地高活生产线启用乐威医药亮相意大利CPHI Milan 2024

临床研究诊断试剂生物类似药上市批准

2024-10-31

·PipelineReview

BridgeBio Oncology Therapeutics (BBOT) Announces First Patient Dosed with First-in-Class BBO-10203, a RAS:PI3Kα Breaker, in the Phase 1 BREAKER-101 Trial for Advanced Solid Tumors

SOUTH SAN FRANCISCO, CA, USA I October 30, 2024 I TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, has announced that the first patient has been dosed with BBO-10203 in the BREAKER-101 trial. BBO-10203 is a first-in-class orally bioavailable RAS:PI3Ka breaker that blocks the interaction between RAS and PI3Kα to inhibit PI3Kα-AKT signaling in tumors, without directly inhibiting the catalytic activity of PI3Kα. “I am thrilled to partner with BBOT to bring a potentially transformable new therapeutic to the clinic,” said Dr. Minal Barve, Chief Medical Officer and Principal Investigator at Mary Crowley Cancer Research, Dallas, TX. “BBO-10203 represents a first-in-class drug with potential to address high unmet medical needs and change the landscape of cancer care. We look forward to evaluating BBO-10203 in the BREAKER-101 trial.” BBO-10203 was designed to bind covalently and selectively to the RAS-binding domain (RBD) of PI3Kα. This selective inhibition is agnostic to the mutational status of PI3Kα and RAS, and in preclinical models, results in complete inhibition of RAS-driven pAKT signal at single digit nanomolar concentration. Additionally, no hyperglycemia was observed in preclinical species treated with BBO-10203. The discovery of BBO-10203 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. “BBO-10203 is a first-in-class program that inhibits the interaction of the two most mutated oncogenes in human cancer, and it will allow us to test, for the first time, the importance of RAS-coordinated activation of the MAPK and AKT signaling pathways,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “The discovery of BBO-10203 was made possible by the dedicated collaboration between academic, national laboratory, and industry experts that synergized to advance medicines for patients suffering from cancer.” The BREAKER-101 trial will enroll patients globally with locally advanced or metastatic HER2-positive breast cancer, HR-positive/HER2-negative breast cancer, KRAS mutant advanced colorectal cancer, and KRAS mutant advanced non-small cell lung cancer. “There is a tremendous opportunity to improve the standard of care in oncology by inhibiting oncogenic pAKT signaling without the metabolic side effects observed with kinase inhibitors, and the initiation of the Phase 1 study of BBO-10203 marks an important milestone in this regard,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “The second IND within six months of establishing BBOT clearly demonstrates our team’s capability in advancing our novel programs into the clinic. This novel mechanism and scientific rationale behind it will allow tremendous combination opportunities that optimally inhibit both pAKT and pERK – an approach we hope will bring unprecedented benefit to patients with RAS-driven cancers.” About TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (BBOT) BridgeBio Oncology Therapeutics (BBOT) is a clinical-stage biopharmaceutical company advancing a next generation pipeline of novel small molecule therapeutics targeting RAS and PI3K malignancies. Initially formed as a subsidiary of BridgeBio, BBOT completed a $200M private financing with external investors in 2024 with the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information visit bridgebiooncology.com . SOURCE: BridgeBio Oncology Therapeutics

临床1期

2024-10-30

·精准药物

【Cancer Discovery】下一代BRAF抑制剂PF-07799933最新数据披露

致癌的BRAF突变根据其作为单体或同源/异源二聚体的活性分为I类（单体）、II类（Ras独立的、组成型激活的二聚体）和III类（Ras依赖性的、低活性二聚体）。目前批准的RAF激酶抑制剂对I类BRAF V600突变体（作为单体发挥作用）有效。尽管可以获得短时间内的有效通路抑制，但长期益处受到几种潜在机制的限制：（1）ERK信号传导的适应性诱导；（2）临床耐药性最常见是由诱导BRAF二聚化的新基因改变引起的；（3）大脑渗透性差，导致颅内疾病进展。此外，批准的RAF抑制剂会导致BRAF野生型细胞中ERK信号的反常激活，从而允许与MEK或表皮生长因子受体（EGFR）抑制剂组合，以减轻由此产生的靶向毒性并提高疗效。然而，联合用药会带来额外的毒性，并且耐药性仍然普遍存在。耐药性改变包括二聚体诱导的BRAF剪接变体、BRAF基因扩增以及BRAF V600突变背景下的RAS突变。由此，下一代BRAF抑制剂的开发已迫在眉睫。 2024年5月1日，来自美国Memorial Sloan Kettering Cancer Center的Rona Yaeger教授团队和Pfizer公司的S. Michael Rothenberg博士团队联合在Cancer Discovery杂志上发表文章A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation。本研究表明下一代BRAF抑制剂PF-07799933在临床前和临床上对于BRAF V600和非V600突变癌症均具有优异的抗肿瘤活性，并且PF-07799933可安全地与MEK抑制剂联合使用。下一代BRAF抑制剂PF-07799933是一款可穿透血脑屏障、选择性的、泛突变体BRAF抑制剂，其可以破坏内源突变体BRAF：野生型CRAF二聚体，并免受野生型ERK信号传导影响。为验证其作用机制，研究团队将PF-07799933与其他多种BRAF/RAF抑制剂针对不同类型的BRAF突变体进行体外分析，结果表明PF-07799933的体外效果优于其他抑制剂，且PF-07799933对于野生型BRAF并无毒性。在IP相互作用分析中发现，相较于BRAF V600单体抑制剂encorafenib，PF-07799933可以有效破坏内源突变体BRAF：野生型CRAF二聚体。随后研究团队利用不同类型的CDx小鼠模型对PF-07799933进行体内抗肿瘤效果评估，结果表明PF-07799933对于BRAF I类、II类和插入/缺失型突变体肿瘤模型均有优异的抗肿瘤活性；而PF-07799933与MEK抑制剂binimetinib联合使用则对于BRAF I类耐药模型具有良好的抗肿瘤活性。在临床前充分验证PF-07799933的作用机制和评估动物肿瘤模型中的优异抗肿瘤活性后，研究团队设计了新颖、快速的基于PK的剂量递增方案开展临床试验。在临床评估中显示，PF-07799933在225 mg BID（每天2次）的剂量下可获得较好的疗效。此外，在本临床试验中，PF-07799933可作为单药使用，也可与MEK抑制剂binimetinib或者EGFR抑制剂cetuximab联合使用。综上所述，本研究表明下一代BRAF抑制剂PF-07799933在临床前和临床上对于BRAF V600和非V600突变癌症均具有优异的抗肿瘤活性，并且PF-07799933可安全地与MEK抑制剂联合使用。此外，研究团队还专门设计了新颖、快速的基于PK的剂量递增方案，为在临床开发早期加速下一代靶向治疗的测试提供了新的范例。原文链接： https://doi-org.libproxy1.nus.edu.sg/10.1158/2159-8290.CD-24-0024 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1期临床2期临床终止