A Randomized Phase 2 Trial to Evaluate the Efficacy of BCL-2 Inhibitor Therapy With Chemotherapy Compared to Chemotherapy Alone in Adult Patients With Newly Diagnosed T-Cell ALL and T-Cell Lymphoblastic Lymphoma

This phase II trial tests the safety and effectiveness of giving chemotherapy with or without venetoclax and/or navitoclax for the treatment of patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax and navitoclax are in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. They may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving chemotherapy with or without venetoclax and/or navitoclax may be effective treatments for patients with newly diagnosed T-ALL or T-LBL.

开始日期2024-08-09

申办/合作机构

National Cancer Institute

NCT05740449 / Withdrawn临床1/2期IIT

International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol A: Decitabine / Venetoclax and Navitoclax in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol A is a phase I/II trial evaluating the safety and efficacy of Decitabine / Venetoclax and Navitoclax in children and AYA with R/R pediatric ALL/LBL

开始日期2023-10-01

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

NCT05864742 / Active, not recruiting临床2期IIT

A Phase II Study of Genetically Risk-Stratified Combination of Venetoclax, Ibrutinib and Rituximab (With and Without Navitoclax) in Patients With Relapsed and Refractory Mantle Cell Lymphoma (AIM2)

This is an open label, multi-centre, phase II study in which RR MCL patients will be genetically risk-stratified into Standard risk (no 9p21.1-24.3 loss, no SMARCA2 or SMARCA4 mut/del) and High risk (9p21.1-24.3 loss, SMARCA2 and/or SMARCA4 mut/del).
Patients without the high-risk mutations will be treated with ibrutinib, rituximab and venetoclax. Patients with the high-risk mutations will be treated with ibrutinib, rituximab, venetoclax and navitoclax.

开始日期2023-09-07

申办/合作机构

Peter MacCallum Cancer Institute

100 项与 Navitoclax 相关的临床结果

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100 项与 Navitoclax 相关的转化医学

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100 项与 Navitoclax 相关的专利（医药）

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699

项与 Navitoclax 相关的文献（医药）

2024-12-01·Purinergic Signalling

Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR

Article

作者: Shatat, Abdel-Aziz S ; Mahgoup, Elsayed M ; Saleh, Ibrahim G ; Rashed, Mohammed H ; Akool, El-Sayed

Abstract:

One of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia‐inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.

2024-12-01·Hepatobiliary & Pancreatic Diseases International

Effects of triggers of senescence and senolysis in murine pancreatic cancer cells

Article

作者: Revskij, Denis ; Fuellen, Georg ; Kölle, Bianca ; Zechner, Dietmar ; Umstätter, Camilla ; Khan, Faiz M ; Jaster, Robert ; Woitas, Aline

BACKGROUND:

The combination of senescence triggers with senolytic drugs is considered a promising new approach to cancer therapy. Here, we studied the efficacy of the genotoxic agent etoposide (Eto) and irradiation in inducing senescence of Panc02 pancreatic cancer cells, and the capability of the Bcl-2 inhibitor navitoclax (ABT-263; Nav) to trigger senolysis.

METHODS:

Panc02 cells were treated with Eto or irradiated with 5-20 Gy before exposure to Nav. Cell survival, proliferation, and senescence were assessed by trypan blue staining, quantification of DNA synthesis, and staining of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, respectively. Levels of mRNA were determined by real-time polymerase chain reaction, and protein expression was analyzed by immunoblotting. Panc02 cells were also grown as pancreatic tumors in mice, which were subsequently treated with Eto and Nav.

RESULTS:

Eto and irradiation had an antiproliferative effect on Panc02 cells that was significantly or tendentially enhanced by Nav. In vivo, Eto and Nav together, but not Eto alone, significantly reduced the proportion of proliferating cells. The expression of the senescence marker γH2AX and tumor infiltration with T-cells were not affected by the treatment. In vitro, almost all Eto-exposed cells and a significant proportion of cells irradiated with 20 Gy were SA-β-Gal-positive. Application of Nav reduced the percentage of SA-β-Gal-positive cells after irradiation but not after pretreatment with Eto. In response to triggers of senescence, cultured Panc02 cells showed increased protein levels of γH2AX and the autophagy marker LC3B-II, and higher mRNA levels of Cdkn1a, Mdm2, and PAI-1, while the effects of Nav were variable.

CONCLUSIONS:

In vitro and in vivo, the combination of senescence triggers with Nav inhibited tumor cell growth more effectively than the triggers alone. Our data also provide some evidence for senolytic effects of Nav in vitro.

2024-11-01·GENE

Integrated analysis of ferroptosis and stemness based on single-cell and bulk RNA-sequencing data provide insights into the prognosis and treatment of esophageal carcinoma

Article

作者: Qin, Yanru ; Li, Jing ; Wang, Wenjia ; Jia, Yongxu ; Zhang, Daidi ; Sui, Xin ; Xu, Jiayao

BACKGROUND:

Cancer stem cells (CSCs) play a significant role in the recurrence and drug resistance of esophageal carcinoma (ESCA). Ferroptosis is a promising anticancer therapeutic strategy that effectively targets CSCs exhibiting high tumorigenicity and treatment resistance. However, there is a lack of research on the combined role of ferroptosis-related genes (FRGs) and stemness signature in the prognosis of ESCA.

METHODS:

The cellular compositions were characterized using single-cell RNA sequencing (scRNA-seq) data from 18 untreated ESCA samples. 50 ferroptosis-related stemness genes (FRSGs) were identified by integrating FRGs with stemness-related genes (SRGs), and then the cells were grouped by AUCell analysis. Next, functional enrichment, intercellular communication, and trajectory analyses were performed to characterize the different groups of cells. Subsequently, the stem-ferr-index was calculated using machine learning algorithms based on the expression profiles of the identified risk genes. Additionally, therapeutic drugs were predicted by analyzing the GDSC2 database. Finally, the expression and functional roles of the identified marker genes were validated through in vitro experiments.

RESULTS:

The analysis of scRNA-seq data demonstrates the diversity and cellular heterogeneity of ESCA. Then, we identified 50 FRSGs and classified cells into high or low ferroptosis score stemness cells accordingly. Functional enrichment analysis conducted on the differentially up-regulated genes between these groups revealed predominant enrichment in pathways associated with intercellular communication and cell differentiation. Subsequently, we identified 9 risk genes and developed a prognostic signature, termed stem_ferr_index, based on these identified risk genes. We found that the stem-ferr-index was correlated with the clinical characteristics of patients, and patients with high stem-ferr-index had poor prognosis. Furthermore, we identified four drugs (Navitoclax, Foretinib, Axitinib, and Talazoparib) with potential efficacy targeting patients with a high stem_ferr_index. Additionally, we delineated two marker genes (STMN1 and SLC2A1). Particularly noteworthy, SLC2A1 exhibited elevated expression levels in ESCA tissues and cells. We provided evidence suggesting that SLC2A1 could influence the migration, invasion, and stemness of ESCA cells, and it was associated with sensitivity to Foretinib.

CONCLUSION:

This study constructed a novel ferroptosis-related stemness signature, identified two marker genes for ESCA, and provided valuable insights for developing more effective therapeutic targets targeting ESCA CSCs in the future.

项与 Navitoclax 相关的新闻（医药）

2024-12-10

·GlobeNewswire-Health Care

UPDATE - Remedy Plan Therapeutics Showcases Preclinical Data from First-In-Class NAMPT Inhibitor, RPT1G, Demonstrating Synergy with BCL-2 Family Inhibitors in AML at the 2024 ASH Annual Meeting

– RPT1G synergizes with venetoclax to yield an eightfold reduction in AML leukemia burden – RPT1G increases the efficacy of venetoclax in venetoclax-resistant AML cells by fourfold versus venetoclax alone GAITHERSBURG, Md., Dec. 10, 2024 (GLOBE NEWSWIRE) -- Remedy Plan Therapeutics (“Remedy Plan”), a clinical stage pharmaceutical company unlocking the therapeutic potential of NAMPT inhibition, presented new data at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California demonstrating that RPT1G, a first-in-class hyperbolic NAMPT inhibitor, provides an eightfold reduction in acute myeloid leukemia (AML) burden when combined with B-cell lymphoma 2 protein (BCL-2) family inhibitors, including venetoclax, in preclinical models of AML. Remedy Plan's data also showed that treatment with RPT1G alone, RPT1G in combination with venetoclax, and RPT1G in a triple combination with venetoclax and the Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib resulted in a fourfold increase in efficacy in venetoclax-resistant AML cells. “Remedy Plan's preclinical data demonstrating synergy between RPT1G and venetoclax and other BCL-2 family inhibitors, are incredibly exciting,” said Saul Rosenberg, Ph.D., Scientific Advisor to Remedy Plan and former executive director of Oncology Drug Discovery at AbbVie Inc., where he oversaw the preclinical discovery and advancement of the BCL-2 family inhibitors venetoclax and navitoclax to the status of clinical candidate. “This synergy not only underscores the potential of Remedy Plan’s approach to enhance treatment efficacy, but also opens the door to developing novel combination regimens that could improve outcomes for patients facing challenging hematological malignancies." Greg Crimmins, Ph.D., founder and chief executive officer of Remedy Plan, added, “These are important combination data for our lead asset, RPT1G, which complement the single agent preclinical data we’ve generated showing potent anti-tumor activity and further underscores the highly differentiated safety profile of our novel NAMPT inhibitor that allows well-tolerated combination therapy. With Remedy Plan’s first-in-human Phase 1 clinical trial of RPT1G commencing in Australia, we look forward to generating early first-in-human clinical data in the coming weeks.” About AML AML is the most common type of adult acute leukemia that progresses rapidly without treatment. Despite the emergence of new therapy options, most AML patients still face dire prognosis, with a 5-year survival rate of 37.5%. Venetoclax, a current standard of care in AML, has transformed treatment by targeting BCL-2, but its long-term efficacy is limited as many tumors develop resistance, driven in part by NAMPT overexpression. Thus, there is still a large unmet need for therapeutic options that can address resistance mechanisms and improve outcomes for AML patients. About Remedy Plan Therapeutics: Remedy Plan is a clinical stage pharmaceutical company unlocking the therapeutic potential of NAMPT inhibition with a pioneering approach that allows for hyperbolic inhibition of NAMPT. This groundbreaking mechanism of action turns down NAMPT activity, but never fully turns it off. By allowing for NAMPT activity in healthy cells, hyperbolic NAMPT inhibition avoids the on-target toxicities observed by other investigational NAMPT inhibitor therapies. Remedy Plan’s lead drug candidate, RPT1G, is a first-in-class, hyperbolic NAMPT inhibitor that has been granted Human Research Ethics Committee (HREC) approval and has Clinical Trial Notification (CTN) clearance by the Australian Therapeutic Goods Administration (TGA) to commence a first-in-human Phase 1 clinical trial of RPT1G in November 2024. The company has commenced the Phase 1 trial in healthy subjects and expects first-in-human clinical data from the trial in early 2025. NAMPT inhibition is widely recognized as a high-value target for the treatment of cancer, autoimmune and metabolic disease. Remedy Plan’s RPT1G drug candidate and its analogues are being investigated for the potential treatment of hematological malignancies, solid tumors, obesity, and autoimmune disorders. Remedy Plan is dedicated to addressing unmet needs in patients with cancer, autoimmune and metabolic diseases through innovative science. For more information, visit remedyplan.com. Investor and Media Contact:Parisa Moghaddam-Taaheripress@remedyplan.com

临床1期ASH会议

2024-09-03

·动脉网

脱胎于哈佛，诺奖得主参与创立，这家企业用合成生物学+AI制药押注抗衰赛道

在当今生物医药领域的前沿，合成生物学、AI制药正在开辟新的药物发现路径。而合成生物学与AI制药的结合，更为药物研发带来了深远的积极影响。人工智能在药物设计方面的应用，通过预测靶点蛋白的三维结构和药物与蛋白质的相互作用，极大地提升了药物设计的精确度和效率。合成生物学则通过“设计-构建-测试-学习”（DBTL）循环，实现了对生物系统的工程化改造，这种系统化的方法论与AI的数据分析和模式识别能力相结合，进一步加速了药物的发现和开发过程。这场科技革新的浪潮中，Integrated Biosciences公司以其突破性的研究和创新技术脱颖而出。Integrated Biosciences成立于2022年，专注于利用合成生物学和人工智能驱动的小分子药物发现平台，开发针对与年龄、衰老相关疾病的下一代治疗方法。公司由Felix Wong博士和Max Wilson博士领衔创立，不仅汇聚了来自麻省理工学院、哈佛大学和普林斯顿大学的顶尖科学家，更吸引了包括诺贝尔化学奖得主在内的豪华顾问团队，致力于寻求针对老年相关疾病的革命性治疗方案。诺奖得主协助创办，聚焦多种老年疾病随着全球人口老龄化的加剧，与年龄相关的疾病治疗需求日益增长。由此，Integrated Biosciences应运而生，旨在通过合成生物学和AI的协同效应，推动药物发现进程。公司的研究重点在于探索与年龄相关的细胞应激反应，这些反应与多种老年疾病的发展密切相关。通过构建虚拟的细胞应激模型，Integrated Biosciences能够在硅片上模拟复杂的生物过程，进而利用AI的强大计算能力，从庞大的化合物库中筛选出潜在的有效药物分子。 Integrated Biosciences的创始团队比较年轻。联合创始人Felix Wong博士拥有哈佛大学的数学、计算机科学和物理学学位。他曾获得 NIH K25 指导定量研究职业发展奖，并入选2023年福布斯 30 位 30 岁以下医疗保健行业精英榜。另外一位联合创始人兼科学顾问委员会会员Max Wilson博士，自 2018 年起担任加州大学圣巴巴拉分校分子生物学教授，拥有光遗传学、综合应激反应等方面的专业知识，并拥有斯沃斯莫尔学院和普林斯顿大学生物学、生物物理学和生物工程学位。除年轻的创始团队外，Integrated Biosciences配备了十分豪华且经验丰富的科学顾问委员会。 David W.C. MacMillan 博士是普林斯顿杰出大学化学教授，2021年，他被授予诺贝尔化学奖，以表彰他在不对称有机催化发展方面的贡献。MacMillan 拥有加州大学欧文分校和格拉斯哥大学的化学学位，是美国国家科学院院士、皇家学会院士和美国艺术与科学学院院士。同时，他是 Chiromics LLC、Penn PhD LLC、Dexterity Pharma LLC 和 Antenna Bio LLC 的联合创始人，在药物化合物发现与筛选方面拥有深厚的背景。 James J. Collins 博士是麻省理工学院生物工程学教授。他曾获得麦克阿瑟奖和罗德学者称号，拥有圣十字学院和牛津大学的物理学学位，也是美国国家工程院、美国国家医学院和美国国家科学院院士。作为合成生物学领域的先驱，Collins创业经验丰富，是Senti Biosciences、EnBiotix、Synlogic和 Sherlock Biosciences 的联合创始人。其中，Senti Biosciences已是行业内赫赫有名的合成生物学企业。年轻创始团队与成熟科学家、企业家的想法相互碰撞，为Integrated Biosciences站在前沿提供了动力。合成生物学+AI，打造全新小分子药物发现技术平台作为一家刚刚成立两年的公司，Integrated Biosciences目前还在搭建自身的小分子药物发现平台。他们希望以其先进的深度学习模型，提高药物发现的效率，在准确性和预测能力上取得显著进步。据公司官网介绍，Integrated Biosciences专有的合成生物学技术，能够帮助虚拟激活细胞应激反应，发现针对应激细胞的药物，并快速识别药物靶点。细胞应激反应会导致神经退化、癌症、糖尿病、骨关节炎和其他与年龄相关的疾病。利用小分子疗法针对这些应激反应可以改善病情，并有助于调节健康衰老。公司也开发了下一代深度学习方法来识别小分子化合物，加速药物发现工作。就在公司成立1年之际，Integrated Biosciences发布了其基于AI技术平台而收获的新成果。 2023年12月，公司在Nature杂志上发表最新研究成果，展示了其AI平台在发现新型抗生素方面的应用，这一成果不仅是对过去60年抗生素研发历史的一次重大突破，更是AI在药物发现领域应用潜力的有力证明。这篇文章详细介绍了Integrated Biosciences平台在发现解决抗生素耐药性问题的新型小分子抗生素方面的应用。在他们的研究中，研究人员虚拟筛选了超过 1200 万种候选化合物，以确定这类新型抗生素。 Integrated Biosciences 创始成员解释，虽然人工智能影响力很大，但它也受到许多常用的黑盒模型的限制，这些模型混淆了底层的决策过程。通过打开这些黑盒，可以创造更普遍的见解，这些见解可能更有助于加速下一代药物发现方法的使用和开发。因此，在这种开创性的方法中，研究团队利用实验生成的数据训练深度学习模型，预测所有化合物的抗生素活性和毒性。他们从其他领域使用的人工智能中汲取灵感，设计了新模型来解释分子的哪些部分对抗生素活性很重要。最终，一种具有强效抗多重耐药病原体活性的新型抗生素脱颖而出。在一系列实验中，研究人员在 MRSA 感染的小鼠模型中测试了一种候选抗生素，发现它在局部和全身均有效，这表明该化合物可能适合进一步开发用于治疗严重和败血症相关的细菌感染。这也进一步验证了Integrated技术平台的可靠性与先进性。在这一研究成果发表前，2023年5月，公司曾在Nature Aging发布研究成果，文章表示，利用公司开发的图形神经网路，成功筛选出有活性的senolytics（衰老细胞清除剂），并且通过衰老模型试验证明了其效果。 Senolytics 是在不再分裂的衰老细胞中选择性诱导细胞凋亡或程序性细胞死亡的化合物，代表化合物包括达沙替尼、槲皮素、非瑟酮和 ABT-263，热休克蛋白 (HSP)-90 抑制剂、强心苷以及溴结构域和末端结构域 (BET) 家族蛋白抑制剂等。尽管临床结果很有希望，但迄今为止发现的大多数 senolytic 化合物都受到生物利用度差和不良副作用的阻碍，比如非瑟酮 ABT-737生物利用度较低， ABT-263引起血小板减少症和中性粒细胞减少症。 Integrated使用衰老模型（依托泊苷诱导）中筛选的2352 种抗衰老活性化合物训练了一个图形神经网络，并将其应用于预测超过80万种化合物的化学空间中的衰老活性。在策划和测试另外的 266 种化合物后，发现这个神经网络的工作命中率（阳性预测值）提高了6倍，达到 11.6% 。 “治疗与年龄有关的疾病最有希望的途径之一是确定治疗干预措施，选择性地将这些细胞从体内清除，类似于抗生素杀死细菌而不伤害宿主细胞的方式。我们发现的化合物显示出高选择性，以及产生成功药物所需的有利药物化学特性，”Integrated Biosciences 衰老生物学负责人、该出版物的联合第一作者 Satotaka Omori 博士说。“我们相信，使用我们的平台发现的化合物将改善临床试验的前景，并最终帮助老年人恢复健康。” 合作共赢，与多家机构达成战略合作为了进一步扩展技术平台，Integrated Biosciences正在积极拓展合作，为在抗衰老领域的深耕奠定基础。 2024年4月，Integrated Biosciences宣布与患者主导的 Project 8p Foundation 建立战略合作伙伴关系，以改善 8p 染色体重复、缺失和反向重复缺失 (inv/dup/del) 疾病的治疗前景。此次合作将使 Integrated有机会表征和纠正 8p 细胞系中细胞应激反应的失调，为开发一流的疾病修饰疗法铺平道路，这些疗法适用于患有 8p 染色体短臂复杂、百万碱基级重排的 8p 患者。 8p染色体疾病是指由于人类8号染色体短臂（8p）部分或全部缺失所引起的一系列临床症状和表型的总称。其特征是8号染色体的短臂部分或全部缺失，即单体8p。这种缺失可导致生长发育迟缓、智力低下、特殊面容、行为异常，部分患者还会有心脏畸形等表现。由于大量基因缺失或重复，染色体疾病治疗起来十分困难。而Integrated Biosciences的平台是全球有效的针对压力反应的小分子搜索引擎，拥有的候选药物可以很好地改善 8p 患者的生活。可以利用细胞应激反应来减轻 8p 患者通常与加速衰老相关的症状。此外，2024年5月，Integrated Biosciences宣布已加入 Illumina Ventures Labs，将其药物发现引擎与 Illumina 测序相结合。此次合作能够提供资金和科学支持，使 Integrated有望发现和设计通过塑造细胞群的转录组和甲基化组起作用的新型小分子疗法。这些候选药物将适用于不同细胞状态导致的各种疾病，包括与衰老和发育有关的疾病。 Integrated Biosciences 联合创始人 Felix Wong 说：“所有药物的作用都是通过修改细胞成分来实现的，而核酸尤为重要。此次合作是利用小分子系统地靶向不同细胞类型的 RNA 表达和 DNA 修饰的纽带，这样我们就可以精确控制细胞的行为方式。我们将生成前所未有的大规模数据集，提供细胞状态图谱及其改变方法，为治疗与年龄相关的疾病指明方向。” 目前，Integrated Biosciences已经进一步验证，人工智能和可解释的深度学习的整合对于克服医学领域一些最棘手的挑战十分重要。在这些验证研究的基础上，公司准备进一步加快合成生物学和对细胞应激理解的整合，以开发与年龄相关的疾病的新疗法。 *封面图片来源：123rf 如果您想对接文章中提到的项目，或您的项目想被动脉网报道，或者发布融资新闻，请与我们联系；也可加入动脉网行业社群，结交更多志同道合的好友。近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

高管变更微生物疗法

2024-05-06

·精准药物

【JMC】百济神州披露BCL-2-WT/G101V突变抑制剂Sonrotoclax (BGB-11417)的设计开发

2024年5月4日，百济神州公司在Journal of Medicinal Chemistry杂志上发表了以“Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2”为题的文章，该文章介绍了细胞淋巴瘤-2（Bcl-2）选择性抑制剂Sonrotoclax (BGB-11417)的发现，对WT Bcl-2和G101V突变体都有很强的体内外抑制活性。该抑制剂目前处于临床II/III期评估阶段，作为单一疗法和联合疗法使用。细胞凋亡是细胞程序性死亡的一种形式，逃避细胞凋亡对肿瘤的发展和维持至关重要。B细胞淋巴瘤-2（Bcl-2）作为一种抗凋亡蛋白，通过抑制促凋亡蛋白来促进细胞存活。Bcl-2在淋巴恶性肿瘤和一些实体瘤的存活过程中起着主导作用，并经常在这些癌症中高表达，它通过与促凋亡蛋白的BH3结构域结合来封闭促凋亡蛋白，从而发挥其功能。因此，抑制细胞内这些蛋白-蛋白之间的相互作用是针对Bcl-2失调导致的癌细胞异常存活的一种有吸引力的策略。过去二十年，已经报道了很多Bcl-2抑制剂（图1），如S65487（2, I期）、lisaftoclax（APG-2575, 3）、lacutoclax（LP-108, 4）、AZD4320（5, II期）和APG-1252（6, II期）。百济神州公司在Bcl-2/Bcl-xL双重抑制剂ABT-737 (1a)及其口服生物可利用类似物ABT-263 (navitoclax, 1b)的基础上开发出了首个选择性Bcl-2（Bcl-xL-sparing）抑制剂ABT-199（venetoclax, 1c），用于治疗Bcl-2依赖性恶性肿瘤。但ABT-199（venetoclax）有限的效力无法在其他Bcl-2介导的恶性肿瘤（如弥漫性大B细胞淋巴瘤）中产生强而持久的临床益处，而且据报道，多种复发性Bcl-2突变（如G101V）可介导长期治疗后对venetoclax的耐药。图1 选择性的Bcl-2抑制剂化合物结构设计为了合理地设计一种能更有效地抑制WT Bcl-2蛋白和G101V突变的Bcl-2抑制剂，作者分析了已报道的Bcl-2抑制剂的结合模式。这些化合物与Bcl-2的P2和P4口袋（ABT-263，图 2a）或仅与P2口袋（S55746，图 2b）结合，实现了良好的结合亲和力，而且P2口袋相对灵活，可兼容各种结构。此外，Bcl-2 G101V: venetoclax共晶体结构（PDB：6O0L）揭示了G101V突变体经venetoclax处理后获得抗性的分子基础。由于Venetoclax的氯苯分子深深插入P2口袋，当G101突变为体积更大的缬氨酸时，一个关键残基Glu152被推入P2口袋的底部，与氯苯产生立体冲突；这导致Venetoclax与Bcl-2 G101V的结合亲和力下降了约180倍。因此，作者进一步优化该化合物的分子结构，增强该化合物与Bcl-2 WT的结合亲和力，并恢复对突变体（尤其是 G101V）的抑制作用。图2 Bcl-2与(a) ABT-263（PDB ID：4LVT）和(b) S55746（PDB ID：6GL8）的晶体结构结构优化作者最初改变了Venetoclax中的哌啶连接物，以探索P2口袋的容积和灵活性，并以Bcl-2 WT为重点进行初步SAR研究。化合物7（图 3）中的长扭曲连接体双环四氢吡唑并[1,5-a]嘧啶在Bcl-2 WT生化实验中具有良好的药效（IC50 = 45 nM），表明P2口袋具有较大的容积和灵活性。过去除二甲基环己烯基团以大幅缩短化合物8中的连接体，进一步证明了其灵活性，但其效力仅下降了1倍（IC50 = 105 nM）。通过改变过于僵硬或过短的双环连接体，获得化合物9a，其生物活性提高了近4倍。以此为改造方向进一步进行结构优化。图3 起始化合物7, 8, 9a的结构优化首先，作者探索了9a中的对氯苯部分对Bcl-2 WT和Bcl-xL及RS4;11和MOLT-4细胞的影响，进行了一系列的结构优化。其中，具有环丙基的化合物9s是最有效的类似物（图4A）。随后作者在9s基础上进行linker的优化，设计并合成了一系列具有不同linker的化合物（图4B）。引入了一种更坚硬的螺连接体7-氮杂螺[3.5]壬烷，生成化合物10r，其生化效力显着提高到0.049 nM，细胞效力增加到5.8 nM。S对映异构体（S-10r）的效力是相应的R对映异构体（R-10r）的∼31倍（0.039 nM vs 1.2 nM）。与Bcl-2蛋白的结合模式分析表明，S-10r的环丙基和吡咯烷基团之间的中心苯环浅结合，并与Met115的侧链形成磺酰基-π相互作用（图5），这有助于提高对Bcl-xL的选择性。S-10r的环丙基诱导P2残基形成不同的构象，包括Asp111、Phe112和Met115，从而产生额外的子口袋。这些额外的疏水相互作用有助于提高S-10r的效力。与Venetoclax相比，S-10r对Bcl-2 G101V的生化效力显著提高（1.3 nM vs 25 nM）图4 不同左侧基团的结构优化（A）和linker的优化（B）图5 （a）S-9c与Venetoclax和（b）S-10r与Venetoclax的晶体结构叠加。（c）S-10r与Bcl-2结合模式随后，作者用S-10r进一步修饰P2口袋的结合基团，以进一步提高对G101V的效力。在一系列优化的化合物中，异丙基类似物11g的效力最高（图6）。为了确定环丙基（S-10r）、异丙基（11g）和N,N-二甲氨基（11n）之间的最佳邻位取代基，作者进一步比较了它们的肝微粒体（LM）稳定性和CYP抑制曲线（表1）。其中，11g在所有评估物种中具有更均衡的LM稳定性和最低的人体CLint以及最弱的CYP2C9抑制性。最后，为了降低DDIs的风险并进一步提高WT Bcl-2和G101V突变体的效力，作者基于先导化合物11g筛选了各种右侧基团优化的化合物。反式异构体12e（也称为BGB-11417）在生化测定中显示出改进的IC50，对Bcl-2 WT和G101V的效力分别为0.019和0.34 nM。当1,4-二氧六环掺入右侧时，作者发现S对映异构体（12h）对CYP2C9没有明显的抑制作用。初步SAR研究表明，化合物12e具有最佳的生化活性和细胞效力。化合物12e与G101V突变体保持强相互作用，表面等离子体共振（SPR）测定（KD = 0.24 nM），而Venetoclax的KD值为29 nM。同时，化合物12e比其他临床Bcl-2选择性抑制剂更有效（表2）。表1 肝微粒体稳定性与CYP抑制作用的比较图6 基于S-10r进行P2口袋的结合基团优化（A）和右侧基团的优化（B）表2 化合物12e比其他临床Bcl-2选择性抑制剂更有效体外研究新型Bcl-2 抑制剂12e的药物特性12e除了不抑制各种CYP酶所表明的低DDI风险外，还在所有四种常见物种中表现出良好的体外肝微粒体稳定性，其中小鼠的CLint仍然最高。随后进一步研究了动物的药代动力学（PK）。总体而言，12e在小鼠和狗体内均表现出良好的PK曲线。由于狗的固有清除率低于小鼠（12e为28.9 vs 48.7），狗的体内清除率也远低于小鼠。因此，狗的Cmax和AUC远高于小鼠，口服的生物利用度也是如此。表3 12e与12h的类药性比较体内PD和疗效研究单剂量口服12e可显著诱导肿瘤中已裂解的caspase-3的表达，由于其出色的体外药效以及在血浆和肿瘤中可接受的暴露量（图7）。在RS4;11携带NCG小鼠体内评估了化合物12e的体内疗效（图8）。化合物12e在7.5 mg/kg的较低剂量下表现出了良好的耐受性和显著的抗肿瘤活性。在治疗后21天的平均肿瘤生长抑制（TGI）值为103%，而venetoclax仅显示出中度的肿瘤生长抑制（TGI为86%）。在对venetoclax不敏感的模型中，12e的效力显著改善，并在DLBCL异种移植模型和RS4;11 Bcl-2 G101V异种移植模型中显示出显著优于venetoclax的PD和疗效。同时，12e对血液系统肿瘤，包括部分NHL有较好的疗效，并有可能克服Bcl-2 G101V突变和其他可能的突变。图7 单次口服12e、12h和venetoclax（50 mg/kg）后，在携带RS4;11异种移植肿瘤的NCG小鼠体内测定的PD/PK数据图8 口服RS4后12e、12h和venetoclax的体内异种移植物活性总结本文开发了一种高效的选择性Bcl-2抑制剂BGB-11417 (12e, sonrotoclax)，该抑制剂可与Bcl-2蛋白的P2口袋形成浅而广泛的相互作用。通过与Bcl-2的共晶体结构，初步确定了一个新的邻位上有烷基取代的苯基吡咯烷片段可以与P2口袋进行相互作用。随后对Linker进行筛选获得了刚性的螺旋连接子7-azaspiro[3.5]壬烷。然后对P2口袋结合部分及右侧基团进一步进行优化，得到化合物BGB-11417 (12e)，其对野生型Bcl-2和G101V突变体以及其他突变体的体外抑制活性均优于venetoclax，且选择性优于Bcl-xL。BGB-11417在异种移植小鼠模型中显著更高的疗效进一步证明了其对venetoclax的优越性。目前，BGB-11417已在ⅰ/ⅱ期临床试验中显示出良好的安全性，并进入ⅲ期临床试验进一步评估其单药及联合治疗CLL、NHL等血液系统恶性肿瘤患者的疗效和安全性。原文链接：https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00027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

100 项与 Navitoclax 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09935	Navitoclax	-	DB12340

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
骨髓纤维化	临床3期	美国	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	日本	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	澳大利亚	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	奥地利	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	比利时	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	保加利亚	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	加拿大	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	克罗地亚	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	捷克	AbbVie, Inc.	2020-08-31
骨髓纤维化	临床3期	丹麦	AbbVie, Inc.	2020-08-31

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASH2024	N/A	急性髓性白血病	-	Navitoclax/Venetoclax/Decitabine Combination	鬱艱範築壓網網襯壓鏇(鏇網構顧窪觸艱構壓餘) = 窪顧夢齋醖鏇鹹範艱夢選淵願衊簾衊顧築齋襯 (淵繭簾觸鹽鏇齋積艱願 )	-	2024-12-09
ASH2024	N/A	难治性白血病	-	Navitoclax (NAV)	簾鹽簾夢鏇願簾選製遞(壓顧觸遞鹹構鹽膚積艱) = One death occurred due to respiratory failure in a R/R MDS subject in C2 膚廠憲齋選夢艱糧鹽鏇 (淵淵蓋憲蓋憲觸廠壓簾 ) 更多	-	2024-12-09
NCT04472598 (TRANSFORM-1, EHA2024) 人工标引	临床3期	骨髓纤维化	252	Navitoclax+Ruxolitinib	衊繭鑰醖壓襯夢選餘艱(構廠憲窪遞網簾鑰鹽繭) = 艱鹹積範蓋醖網鏇廠選選鬱積築壓積範醖構範 (淵選壓糧糧鑰襯構衊醖 ) 达到更多	积极	2024-05-14
NCT04472598 (TRANSFORM-1, EHA2024) 人工标引	临床3期	骨髓纤维化	252	Placebo+Ruxolitinib	衊繭鑰醖壓襯夢選餘艱(構廠憲窪遞網簾鑰鹽繭) = 積觸廠顧選繭壓繭願鬱選鬱積築壓積範醖構範 (淵選壓糧糧鑰襯構衊醖 ) 达到更多	积极	2024-05-14
NCT04472598 (TRANSFORM-1, ASH2023)	临床3期	原发性骨髓纤维化	252	Navitoclax + Ruxolitinib	醖襯獵積築構蓋蓋鹹襯(蓋築鑰鹽鹹淵鹹夢壓醖) = 衊鹽鏇衊顧廠膚艱遞襯蓋淵簾網選壓範蓋獵鏇 (鹽獵願獵憲選製積選繭 ) 更多	积极	2023-12-10
NCT04472598 (TRANSFORM-1, ASH2023)	临床3期	原发性骨髓纤维化	252	Placebo + Ruxolitinib	醖襯獵積築構蓋蓋鹹襯(蓋築鑰鹽鹹淵鹹夢壓醖) = 廠醖積鬱淵觸憲遞夢襯蓋淵簾網選壓範蓋獵鏇 (鹽獵願獵憲選製積選繭, 16.8 ~ NR) 更多	积极	2023-12-10
SOHO2023	N/A	骨髓纤维化	-	Navitoclax	積衊遞鹽淵艱淵壓鬱壓(範淵餘齋積窪選壓網觸) = 43% (Grade ≥3: 34%) 憲網獵淵鹹顧淵遞淵窪 (繭網鏇襯製遞醖壓壓廠 ) 更多	-	2023-09-01
SOHO2023	N/A	骨髓纤维化	-	Ruxolitinib		-	2023-09-01
LBA 12 (SGO)	临床1/2期	女性生殖器官肿瘤 RAS-mutated	31	Trametinib and Navitoclax	構遞網願繭鬱壓築鏇範(網壓醖醖鑰鹽醖夢鬱廠) = 積選鹽艱淵艱衊淵觸獵窪網窪繭醖築願壓鏇簾 (膚鹹積齋鑰獵網簾壓積, 17.5 ~ 57.9) 更多	积极	2022-08-01
NCT03222609 (ASCO2022) 人工标引	临床2期	骨髓纤维化	32	Navitoclax + Ruxolitinib	壓襯願糧壓餘鹽淵獵淵(簾壓衊遞獵鬱鏇憲齋顧) = 積憲蓋窪鹽鹽網艱糧醖觸襯淵壓願積範艱艱壓 (願獵窪齋繭願鹹選觸廠 ) 更多	积极	2022-06-02
NCT03222609 (REFINE, Pubmed) 人工标引	临床2期	原发性骨髓纤维化	34	ruxolitinib+navitoclax	壓獵範襯醖觸淵餘願鏇(顧衊鹽觸簾築築觸範獵) = 簾衊範構艱齋齋製鏇憲衊築觸遞積構簾齋衊醖 (夢廠襯襯鏇膚構窪鹽選 ) 更多	积极	2022-02-18
NCT03222609 (EHA2021)	临床2期	JAK-2 V617F阳性骨髓增生性疾病	34	Navitoclax plus Ruxolitinib	顧願選製鏇網鏇構觸獵(鹽遞範觸艱夢繭鏇獵簾) = thrombocytopenia (without clinically significant bleeding; 56%) and anemia (32%) 網範選廠窪範簾築鹹鬱 (願鬱艱窪齋簾選壓獵夢 ) 更多	-	2021-06-09
NCT00888108 (Pubmed \| Ann Oncol)	临床1期	晚期恶性实体瘤	41	Navitoclax plus docetaxel	(網衊獵艱鹹醖鑰繭簾蓋) = 61% 製艱鹽鑰憲獵顧淵艱簾 (願襯餘齋觸鏇鏇襯選衊 ) 更多	-	2021-04-14