This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

开始日期2013-10-30

申办/合作机构

National Cancer Institute

NCT01979523

/ Completed临床2期IIT

A Randomized Two-Arm Phase II Study of Trametinib Alone and in Combination With GSK2141795 in Patients With Advanced Uveal Melanoma

This randomized phase II trial studies how well trametinib with or without Akt inhibitor GSK2141795 (GSK2141795) works in treating patients with uveal melanoma that has spread to other parts of the body (metastatic). Trametinib and GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective with or without GSK2141795 in treating patients with metastatic uveal melanoma.

开始日期2013-10-23

申办/合作机构

National Cancer Institute

NCT01902173

/ Completed临床1/2期IIT

Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib in Patients With BRAF Mutant Cancer

This phase I/II trial studies the side effects and the best dose of uprosertib when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IIIC-IV cancer. Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with dabrafenib and trametinib may be a better treatment for cancer.

开始日期2013-10-08

申办/合作机构

National Cancer Institute

[+2]

100 项与 Uprosertib 相关的临床结果

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100 项与 Uprosertib 相关的转化医学

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100 项与 Uprosertib 相关的专利（医药）

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项与 Uprosertib 相关的文献（医药）

2025-04-01·Molecular Diversity

An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs

Article

作者: Kuchana, Vinutha ; Etikyala, Umadevi ; Dalimba, Udayakumar ; Reddyrajula, Rajkumar ; Vani, T ; Manga, Vijjulatha

Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R² and Q² values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

2025-02-01·Breast Cancer Research and Treatment

Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer

Article

作者: Prasath, Vishnu ; Villalona-Calero, Miguel ; Abdel-Rasoul, Mahmoud ; Poklepovic, Andrew ; Perou, Charles M ; Boutrid, Hinda ; Dees, Claire ; Wesolowski, Robert ; Johnson, Gary L ; Mrozek, Ewa ; Lustberg, Maryam ; Harris, Lyndsay ; Shapiro, Charles ; Isaacs, Claudine ; Layman, Rachel M ; Glover, Kristyn ; Timmers, Cynthia ; Vater, Mark ; Ramaswamy, Bhuvaneswari ; Stover, Daniel G ; Chen, Helen ; Carson, William ; Budd, G Thomas ; Macrae, Erin

PURPOSEWhile MEK inhibitors demonstrated activity in metastatic triple negative breast cancer (mTNBC) preclinical studies, preclinical, and clinical studies implicate rapid development of resistance limiting clinical benefit. The purpose of this study was to determine response rate for Trametinib alone and in combination with Uprosertib in patients with mTNBC previously treated with chemotherapy.METHODSThis was an open-label, two-part, phase II, single-arm, multicenter study. Patients first received Trametinib monotherapy (2 mg daily; Part I) then at progression transitioned to Trametinib (1.5 mg) plus Uprosertib (50 mg; Part II).RESULTSBetween October 2013 and January 2017, 37 patients were enrolled to Part I. Subsequently, 19 patients entered Part II. Of the 37 patients receiving Trametinib monotherapy, 2 patients achieved partial response (PR) for an ORR of 5.4% (2/37) and an additional 6/37 (16.2%) achieved stable disease (SD). The clinical benefit rate (PR+SD) for patients receiving monotherapy was 21.6% (8/37). Of the 19 patients in Part II, 3 patients achieved PR for an ORR to Part II of 15.8% (3/19) and an additional 3 achieved SD. Median progression-free survival (PFS) was 7.7 weeks for Part I and 7.8 weeks for Part II. Circulating tumor DNA (ctDNA) clearance at C2D1 of Trametinib monotherapy was associated with improved PFS and overall survival.CONCLUSIONIn patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response.

2025-02-01·Advanced Functional Materials

Advanced Hierarchical Computational Modeling‐Based Rational Development of Platinum (II) Nanocomplex to Improve Lung Cancer Therapy

作者: Chen, Shangyu ; Chen, Yuang ; Burns, Timothy F. ; Yang, Da ; Huang, Yixian ; Huang, Haozhe ; Li, Sihan ; Bain, Daniel J. ; Wang, Junmei ; Li, Song ; Ji, Beihong ; Li, Shichen ; Sun, Jingjing ; Luo, Zhangyi

AbstractCancer stem cells (CSCs) are known to be one of the determining factors that contribute to therapeutic resistance. However, much remains to be understood about the reprogramming network leading to the generation of CSCs driven by chemotherapy. In this study, guided by bioinformatics study, deeper insight is uncovered and provided into the CSC enrichment mechanism driven by cisplatin (CDDP) treatment. It is discovered that CDDP can repopulate the level of CSC by activating AKT1 oncogenic pathway that is further enhanced by COX‐2 inflammatory signaling. Simultaneously blocking these two pathways can synergistically restrain the number of CSCs. Under the guidance of advanced hierarchical computational modeling, including molecular docking, molecular dynamics (MD) simulation and binding free energy analysis, MK‐2206 is selected as the AKT1 inhibitor to achieve optimal codelivery of CDDP, MK‐2206 and 5‐ASA (COX‐2 inhibitor) through 5‐ASA‐derivatized dual functional immunostimulatory nanocarrier (PASA). This triple combination (PASA/CDDP/MK‐2206) significantly reduces tumor burden in both orthotopic and metastatic lung cancer models. Mechanistic studies show that this improved therapeutic activity is due to elimination of CSCs and reversal of the immunosuppressive tumor microenvironment. This study suggests that PASA/CDDP/MK‐2206 may represent a simple and effective lung cancer therapy via reversing CSCs‐associated chemoresistance.

项与 Uprosertib 相关的新闻（医药）

2025-03-15

·精准药物

【JMC】丁克/王震等报道新型不可逆CDK12/13抑制剂YJZ5118

近日，上海有机所丁克研究员/王震研究员联合密歇根大学团队在国际顶级药物化学期刊《Journal of Medicinal Chemistry》上发表题为“发现YJZ5118：一种与Akt抑制剂联合使用时具有协同效应的强效且高选择性不可逆CDK12/13抑制剂”的研究论文。该研究聚焦于CDK12/13这一新兴癌症治疗靶点，开发了一种新型不可逆抑制剂YJZ5118，并揭示其与Akt抑制剂的协同抗肿瘤效应。实验表明，YJZ5118可有效抑制RNA聚合酶II的Ser2磷酸化，抑制DNA损伤响应基因的转录，诱导DNA损伤和细胞凋亡。此外，YJZ5118在多种肿瘤细胞系中展现出显著的抗增殖效果，尤其对前列腺癌和乳腺癌细胞敏感。更重要的是，YJZ5118与Akt抑制剂联合使用时，在体外和体内模型中均表现出协同抗肿瘤效应，为癌症治疗提供了新的联合用药策略。图片来源：ACS 01 Background 研究背景 CDK12和CDK13作为转录相关激酶，在DNA损伤响应（DDR）和基因组稳定性维持中起关键作用。它们通过磷酸化RNA聚合酶II的C末端结构域（CTD）的Ser2位点来调控转录延伸、剪接以及切割和聚腺苷酸化过程。近年来，CDK12/13因其在多种人类癌症中的潜在治疗价值而备受关注，尤其是在去势抵抗性前列腺癌（CRPC）和三阴性乳腺癌（TNBC）中，抑制这些激酶的活性或表达已被证实可以显著抑制癌细胞的增殖。此外，CDK12的突变在转移性CRPC患者中占5%~7%，且CDK12突变可能作为CDK12/13降解剂的协同生物标志物。尽管如此，目前开发的CDK12/13抑制剂仍面临活性、选择性、药代动力学（PK）特性以及安全性之间的平衡挑战，且缺乏足够的体内疗效数据，尚未有药物进入临床试验阶段。因此，开发具有替代化学骨架的新型不可逆CDK12/13抑制剂对于进一步验证选择性抑制CDK12/13作为癌症治疗策略具有重要意义。图片来源：ACS 02 Drug Design 药物设计与评价 ①药物设计作者描述了基于结构的药物设计过程，旨在开发一种新型的不可逆CDK12/13抑制剂。研究团队从一种可逆的CDK12/13抑制剂（化合物2）出发，该化合物具有较强的酶抑制活性和良好的激酶选择性，但对CDK7和CDK9的选择性较弱。通过对化合物2与CDK12/CCNK复合物的共晶结构分析，结合已知的共价抑制剂THZ531的结构信息，研究团队推测可以通过在化合物2的中心苯环上引入丙烯酰胺弹头，使其能够与CDK12的Cys1039共价结合，从而实现不可逆抑制。此外，为了促进共价键的形成并改善药物的水溶性和药代动力学特性，研究团队在丙烯酰胺弹头附近引入了亲水性的烷基胺基团。图片来源：ACS ②构效关系研究作者详细描述了通过一系列结构优化发现新型不可逆CDK12/13抑制剂YJZ5118（化合物14k）的过程。研究团队以可逆抑制剂2为先导化合物，通过在其结构基础上引入丙烯酰胺弹头和不同的烷基胺基团，合成了多个衍生物，并对它们的CDK12/13抑制活性、细胞增殖抑制活性以及药代动力学特性进行了评估。结果显示，化合物14a表现出与先导化合物2相当的CDK12/13抑制活性，但细胞增殖抑制活性显著增强，表明其可能通过共价结合延长了靶点占据时间。进一步的结构优化中，化合物14h表现出最强的激酶抑制活性和细胞活性，但其体内药代动力学特性不佳。最终，通过引入4-(二甲氨基)哌啶基团，化合物14k（YJZ5118）在保持较高激酶抑制活性的同时，展现出显著改善的药代动力学特性，包括较高的口服生物利用度和较长的半衰期。此外，YJZ5118对CDK12/13的选择性超过100倍，对其他CDK家族成员的抑制作用较弱，仅对CDK7表现出中等抑制活性。这些结果表明，YJZ5118作为一种新型的不可逆CDK12/13抑制剂，具有良好的靶点选择性、细胞活性和药代动力学特性。图片来源：ACS 03 In vitro In Vivo 体内外评价 ①YJZ5118共价结合模式的验证作者通过多种实验手段验证了YJZ5118与CDK12/13的共价结合模式。首先，通过液相色谱-质谱（LC-MS）分析，观察到CDK12与YJZ5118孵育后出现了与YJZ5118分子量一致的质量偏移，证实了化合物与CDK12的共价结合。进一步，通过解析YJZ5118与CDK12/CCNK复合物的共晶结构（分辨率2.5 Å），研究团队发现YJZ5118的丙烯酰胺基团与CDK12的Cys1039形成了共价键，同时化合物的其他部分通过氢键与激酶的关键氨基酸残基相互作用。此外，为了在细胞环境中验证共价结合，研究团队合成了YJZ5118的生物素标记探针YJZ9149，并利用链霉亲和素（streptavidin）珠子进行下拉实验，结果表明CDK12和CDK13是细胞裂解液中与YJZ5118共价结合的主要蛋白。最后，通过细胞洗脱实验比较了YJZ5118与可逆抑制剂在细胞中的作用持久性，发现YJZ5118即使在移除药物后仍能长时间抑制细胞增殖和RNA聚合酶II的Ser2磷酸化，而可逆抑制剂的作用则迅速消失。这些结果共同证实了YJZ5118通过共价结合不可逆地抑制CDK12/13的活性，为其作为不可逆抑制剂的特性提供了有力的证据。图片来源：ACS ②YJZ5118在多种癌细胞系中对DNA损伤响应（DDR）基因转录的抑制作用，以及其诱导DNA损伤和细胞凋亡的能力实验结果显示，YJZ5118能够以剂量和时间依赖的方式抑制RNA聚合酶II的Ser2磷酸化，进而影响依赖于该位点磷酸化的转录延伸过程。通过RNA测序（RNA-seq）分析，研究发现YJZ5118处理的细胞中，基因长度与基因表达下调之间存在显著相关性，较长的基因更倾向于被抑制，这与CDK12在转录调控中的作用机制一致。此外，YJZ5118显著降低了多个DDR相关基因（如ATM、ATR、RAD51和FANC1）的表达水平，而对其他非DDR相关基因（如NRAS和EZH2）的影响较小。为了进一步验证YJZ5118诱导的DNA损伤，研究团队采用中性彗星实验检测了细胞中的DNA断裂情况，结果表明YJZ5118处理的细胞中DNA损伤显著增加。同时，流式细胞术分析显示YJZ5118能够诱导细胞凋亡，且在100 nM的浓度下即可显著提高细胞的凋亡率。此外，YJZ5118在多种肿瘤细胞系（包括前列腺癌、乳腺癌和尤文氏肉瘤细胞系）中展现出显著的细胞毒性，而对正常和非癌性细胞的敏感性较俴e。这些结果表明，YJZ5118通过抑制CDK12/13的活性，有效地抑制了DDR基因的转录，诱导了DNA损伤和细胞凋亡，且对多种癌细胞系具有选择性的抗增殖活性，而对正常细胞的影响较小，这为其作为潜在的抗癌药物提供了重要的生物学依据。图片来源：ACS ③YJZ5118与Akt抑制剂联合使用在体内外均显示出协同作用。研究团队探讨了YJZ5118与Akt抑制剂联合使用时的协同抗肿瘤效果。实验发现，YJZ5118单独处理细胞时会增加Akt及其底物PRAS40的磷酸化水平，提示CDK12/13的抑制可能通过某种机制激活Akt信号通路。基于此，研究团队将YJZ5118与多种Akt抑制剂（如MK2206、uprosertib、ipatasertib和afuresertib）联合应用于22RV1前列腺癌细胞系，并通过Loewe协同效应分析法评估了联合用药的协同性。结果显示，YJZ5118与Akt抑制剂的组合在体外实验中表现出显著的协同抑制细胞生长的效果，其中与MK2206的联合治疗协同得分达到10.81。进一步的体内实验采用VCaP去势抵抗性前列腺癌（CRPC）小鼠模型，通过腹腔注射YJZ5118和口服给予uprosertib的方式进行联合治疗。结果表明，与单独用药相比，联合治疗显著抑制了肿瘤生长，且未引起明显的体重变化或其他不良反应。治疗结束时的肿瘤分析显示，YJZ5118有效抑制了RNA聚合酶II的Ser2磷酸化，增加了pAkt（S473）和pPRAS40的水平，并降低了DDR基因的表达，同时增强了细胞凋亡。这些结果表明，YJZ5118不仅能够通过抑制CDK12/13引发Akt磷酸化，还能与Akt抑制剂联合使用，展现出显著的协同抗肿瘤效果，为开发新的联合治疗策略提供了有力的实验依据。图片来源：ACS 总结研究团队从可逆抑制剂2出发，通过结构优化开发了YJZ5118。该化合物展现出显著增强的抗增殖活性和对CDK12/13的高选择性。通过质谱分析、共晶结构研究和蛋白质组学实验，YJZ5118的共价结合模式得到了全面验证。功能实验表明，YJZ5118能够有效抑制RNA聚合酶II的Ser2磷酸化，抑制DNA损伤响应基因的转录，并诱导DNA损伤和细胞凋亡。此外，YJZ5118在多种肿瘤细胞系中表现出显著的抗增殖效果，而对正常和非癌性细胞的影响较小。值得注意的是，YJZ5118能够诱导Akt磷酸化，并且与Akt抑制剂联合使用时，在体外和体内均展现出协同抗肿瘤效果。这些结果突显了YJZ5118作为癌症治疗策略的潜力，为未来进一步的临床研究提供了重要基础。参考来源： https://doi.org/10.1021/acs.jmedchem.5c00127 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↓

寡核苷酸

2024-10-10

·精准药物

丁克团队等2连发：口服CDK12降解剂的开发及在前列腺癌中的潜在应用

近年来，CDK12基因突变型前列腺癌（PCa）的研究揭示了其与基因组不稳定性及耐药性密切相关。然而，CDK12突变是如何驱动癌症发展的具体机制仍未得到充分理解。为解决这一科学难题，中国科学院上海有机化学研究所丁克研究员与密歇根大学Rogel癌症中心Arul Chinnaiyan教授通过合作，分别于2024年9月30日和10月4日在Cell子刊Cell Reports Medicine杂志背靠背发表两篇关于CDK12的前沿研究，不仅在理论上揭示了CDK12突变驱动癌症发展的具体机制，还提出了具有应用潜力的治疗策略，极大地推动了前列腺癌领域的研究进展。 CDK12缺失驱动前列腺癌进展的分子机制 1. CDK12缺失引发前癌性病变和T 细胞浸润在CDK12缺失小鼠模型中，前列腺上皮细胞出现显著的前癌性病变，并伴随T细胞浸润（CD3+T细胞显著增加），提示局部免疫微环境的改变。γH2AX 标记显著上升，表明DNA损伤增加。Ki67阳性细胞增多则显示出增殖活性增加。这些结果表明CDK12缺失能够推动前癌性病变和免疫浸润，进一步促进癌变发展。 2. CDK12缺失通过转录-复制冲突（TRCs）导致基因组不稳定 RNA-seq和ChIP-seq数据表明，CDK12缺失的前列腺类器官中存在大范围的TRCs和基因组不稳定性。基因组水平上，DDR基因（BRCA1、ATM）表达显著下调，而DNA断裂数量显著增加。通过中性彗星实验和细胞周期分析显示，CDK12缺失细胞中的DNA损伤和G1/S阻滞显著升高，揭示了TRCs是推动前列腺癌发展及基因组不稳定性的关键机制。 3. CDK12/Trp53双敲除小鼠模型对免疫检查点抑制剂的敏感性 CDK12和Trp53双敲除小鼠表现出高度侵袭性的前列腺癌，且在PD-1 抑制剂（如Nivolumab）治疗下显示出显著的肿瘤缩小效果（肿瘤体积缩小超过50%）。CD8+T细胞浸润显著增加，表明CDK12/Trp53双突变模型对免疫治疗响应率较高。这一发现提示免疫检查点抑制剂联合CDK12靶向治疗可能是治疗这一亚型前列腺癌的有效策略。 4. CDK12缺失导致对同源基因CDK13靶向治疗的合成致死效应通过CRISPR筛选和基因敲除实验，CDK13抑制在CDK12缺失细胞中引发的合成致死效应显著增加，诱导细胞凋亡（Caspase-3活性显著上升），而未在野生型细胞中观察到。这表明靶向CDK13的策略可以在CDK12突变型前列腺癌中实现合成致死，为联合靶向治疗提供了实验依据。 CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13 开发新型CDK12/CDK13降解剂YJ1206：精准靶向的治疗新策略 5. 开发新型口服CDK12/CDK13降解剂YJ1206 研究团队通过PROTAC技术设计并优化了新型降解剂YJ1206，能够高效选择性降解CDK12和CDK13。在前列腺癌细胞系（VCaP、22Rv1）中，YJ1206的IC50值分别为33.55nM和85.74 nM，而在正常前列腺上皮细胞中（如 RWPE1）IC50 高于500nM。YJ1206在体内小鼠模型中能够显著抑制肿瘤生长，并降低DNA损伤相关基因（如 BRCA1、ATM）的表达，显示其作为临床候选药物的潜力。 6. YJ1206在多种前列腺癌模型中显示出优异的抗肿瘤活性在体内前列腺癌异种移植小鼠模型（VCaP和22Rv1）中，YJ1206的治疗能够显著抑制肿瘤生长。治疗18天后，73%的小鼠肿瘤体积缩小超过50%。免疫组化分析显示，YJ1206处理后肿瘤组织中DDR相关基因（BRCA1、ATM）表达下降，TUNEL阳性细胞增加，表明其能够有效诱导细胞凋亡。 7. YJ1206与AKT抑制剂联用的合成致死效应在探索CDK12/13降解剂的耐药机制时，研究团队发现YJ1206降解CDK12/13后，AKT信号通路会被激活，导致治疗效果降低。为了克服这一问题，研究团队将YJ1206与AKT抑制剂（如Ipatasertib, Uprosertib, MK2206）联合使用。实验显示，联合治疗能够显著增强YJ1206的抗肿瘤活性，诱导癌细胞凋亡，并减少细胞增殖。这一联合策略在多个小鼠CDX以及PDX异种移植模型中均表现出优异的抗肿瘤效果，联合治疗组肿瘤体积显著缩小，表明该策略能够有效克服YJ1206单药使用时可能出现的耐药性问题。 8. YJ1206 在体内外实验中表现出较少的副作用与其他CDK12抑制剂（如THZ531）相比，YJ1206在体内显示出更好的耐受性和较少的毒性。在小鼠实验中，YJ1206的治疗未导致体重变化和正常组织毒性，同时肿瘤体积显著缩小（P < 0.01），进一步验证了其作为新型抗癌药物的应用潜力。 Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition 研究重大意义与未来展望这两项研究首次揭示了CDK12在前列腺癌进展中的关键作用，并开发了靶向CDK12/13的新型降解剂YJ1206，为CDK12突变相关癌症的精准治疗带来了新的希望。通过揭示CDK12/13在维持基因组稳定性及调控DDR中的冗余作用，研究团队提出了将CDK12/13降解剂与AKT抑制剂联合使用的合成致死策略。这一发现不仅为CDK12突变型前列腺癌的治疗提供了新的思路，也为未来其他癌症的治疗策略开发奠定了基础。正如Arul Chinnaiyan教授所言：“当我们首次发现CDK12突变型前列腺癌这一新的亚型时，我们意识到必须深入了解这种基因变异如何驱动癌症的发展，并寻找精准靶向这一突变的新治疗策略。通过两篇研究论文，我们不仅揭示了CDK12缺失诱导癌症的分子机制，还开发了一种能够同时降解CDK12和CDK13的潜在治疗药物。这项工作展示了跨国、跨学科合作在推动癌症研究和药物开发中的巨大潜力，并为未来的临床应用铺平了道路。”。未来，研究团队将进一步优化YJ1206的药物特性，并计划开展更多的临床前研究，最终将其推进至临床试验阶段，为全球前列腺癌患者提供更为精准和有效的治疗选择。原文链接： https://doi.org/10.1016/j.xcrm.2024.101758 https://doi.org/10.1016/j.xcrm.2024.101752 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↓

2024-01-29

·FierceBiotech

After GSK and Novartis handoffs, Laekna's drug fails ovarian cancer trial

After handoffs from GSK and then Novartis, afuresertib landed at Laekna. Shanghai-based biotech Laekna's oral cancer drug afuresertib has failed to significantly improve progression-free survival for ovarian cancer patients in a phase 2 trial. Originally developed by GSK, afuresertib swapped Big Pharma hands, previously falling under Novartis’ possession until being out-licensed to Laekna in 2018. That deal encompassed two oral pan-Akt kinase inhibitors—afuresertib and uprosertib—both of which originated at GSK. The two drugs have been tested against ovarian and gastric cancers, multiple myeloma, melanoma and other diseases. Now, afuresertib has failed to meet the primary target of a global phase 2 registrational trial in platinum-resistant ovarian cancer (PROC) conducted in the U.S. and China, according to a Jan. 28 release (PDF). The open-label study, dubbed PROFECTA II, assessed afuresertib alongside the chemotherapy paclitaxel in a total of 150 patients. In the study, 94 patients received the investigational combo, while 47 received solo paclitaxel. The drug failed to reach statistical significance on the trial’s primary endpoint of progression-free survival. However, Laekna said a phosphor-AKT positive biomarker subgroup experienced significantly improved PFS, with their median PFS reaching 5.4 months compared to 2.9 months. The biotech reported a manageable and tolerable safety profile, with adverse events consistent with the known safety profiles of the individual treatments. Further data from the trial will be presented at an unnamed medical conference, according to the company release. Laekna said it expects to discuss the results with regulatory authorities in hopes of identifying a registration path for PROC patients who may benefit from afuresertib.

临床2期临床结果临床3期

100 项与 Uprosertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10674	-	-	DB11969

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
皮肤黑色素瘤	临床2期	美国	Novartis Pharmaceuticals Corp.	2013-10-08
皮肤黑色素瘤	临床2期	美国	GSK Plc	2013-10-08
晚期三阴性乳腺癌	临床2期	美国	GSK Plc	2013-10-02
复发性乳腺癌	临床2期	美国	GSK Plc	2013-10-02
浸润性乳腺癌	临床2期	美国	GSK Plc	2013-10-02
转移性乳腺癌	临床2期	美国	GSK Plc	2013-10-02
转移性三阴性乳腺癌	临床2期	美国	GSK Plc	2013-10-02
BRAF突变阳性黑色素瘤	临床2期	美国	The University of California, San Francisco	2013-09-10
成人急性髓性白血病	临床前	美国	National Cancer Institute	2013-10-01
复发性宫颈癌	临床前	美国	Novartis AG	2013-10-01

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临床结果

适应症

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


NCT01138085 (Pubmed) 人工标引	临床1期	实体瘤	126	uprosertib+trametinib	(憲繭獵襯鏇積獵顧窪鬱) = Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. 鹽鑰醖遞餘糧遞餘餘衊 (膚襯夢廠鏇窪製網築鏇 )	不佳	2020-04-01
NCT01964924 (CTgov)	临床2期	复发性乳腺癌 \| 转移性乳腺癌 \| 转移性三阴性乳腺癌 \| 浸润性乳腺癌 \| 晚期三阴性乳腺癌	37	Laboratory Biomarker Analysis+Akt Inhibitor GSK2141795+Trametinib	鏇衊艱鬱憲繭廠構鏇夢(鏇壓齋壓淵窪憲簾糧鬱) = 夢襯範鑰願憲積鑰繭鑰觸簾淵築築網獵遞簾艱 (壓蓋鹹鑰憲積製鹹醖餘, 顧糧積膚衊齋憲範衊齋 ~ 網製顧構製觸積構遞壓) 更多	-	2019-09-20
NCT01907815 (Pubmed \| Clin Lymphoma Myeloma Leuk) 人工标引	临床2期	急性髓性白血病 RAS Mutation	23	Trametinib+GSK2141795	(鏇構醖鬱鹽齋鏇襯製顧) = No complete remissions were identified in either cohort 餘鏇築鹽選襯鏇構繭選 (衊獵鏇壓遞網淵觸窪鏇 ) 更多	积极	2019-07-01
NCT01958112 (Pubmed \| Obstet Gynecol Surv) 人工标引	临床2期	宫颈癌 PI3K \| RAS	14	trametinib+GSK2141795	(淵鏇齋餘襯積簾窪蓋網) = 遞獵積壓顧積鬱廠願壓簾艱鬱齋鏇憲襯夢製鬱 (鹹選積淵遞醖鏇觸醖膚 ) 更多	不佳	2019-07-01
NCT01958112 (CTgov)	临床2期	复发性宫颈癌	14	GSK1120212 (trametinib)+GSK2141795	遞構艱鹹鹽夢壓鬱簾鏇(鹽顧網窪簾繭鹽餘壓構) = 憲觸鏇餘獵鹹襯壓蓋齋齋鬱構襯衊憲憲鏇襯遞 (鑰構鹽獵醖鏇夢鹹獵艱, 夢顧積築艱繭鏇壓簾鹽 ~ 範繭願糧糧鬱鏇齋獵簾) 更多	-	2019-01-02
NCT00920257 (Pubmed \| Invest New Drugs) 人工标引	临床1期	实体瘤	77	GSK2141795	(範繭鑰衊顧醖觸鏇顧齋) = 鹽積繭齋簾鏇憲築艱鏇築鬱積網憲簾製鏇壓繭 (窪廠鹽膚獵繭繭廠壓淵 ) 更多	积极	2018-12-01
NCT01907815 (CTgov)	临床2期	成人急性髓性白血病	24	GSK2141795+Trametinib (Trametinib 2.0 mg + GSK2141795 25 mg)	廠遞鹹壓構鹹鑰壓蓋糧(廠繭衊艱窪壓憲觸範鹹) = 範築蓋壓醖艱網觸鹽鹹壓壓糧製鹽遞窪衊糧壓 (蓋構願齋範衊製遞簾夢, 廠構鑰淵餘鹹鹽夢鬱簾 ~ 構鑰構淵餘襯簾積廠鏇) 更多	-	2018-04-06
NCT01907815 (CTgov)	临床2期	成人急性髓性白血病	24	GSK2141795+Trametinib (Trametinib 1.5 mg + GSK2141795 50 mg)	廠遞鹹壓構鹹鑰壓蓋糧(廠繭衊艱窪壓憲觸範鹹) = 範構醖醖膚遞鏇鏇夢選壓壓糧製鹽遞窪衊糧壓 (蓋構願齋範衊製遞簾夢, 鹽構鑰艱顧範觸簾醖築 ~ 齋夢膚鑰鑰齋醖鹹遞鏇) 更多	-	2018-04-06
NCT01941927 (Pubmed \| Pigment Cell Melanoma Res) 人工标引	临床2期	NRAS突变黑色素瘤 NRAS Mutation \| BRAF Wild-type \| NRAS Wild-type	20	trametinib+GSK2141795 (NRAS-mutant patients)	(壓獵遞廠壓鹹築積鬱顧) = No objective responses were noted in either cohort. 憲憲襯艱膚築願襯遞鑰 (齋襯獵鬱獵願衊範鑰築 ) 更多	不佳	2018-01-01
NCT01941927 (Pubmed \| Pigment Cell Melanoma Res) 人工标引	临床2期	NRAS突变黑色素瘤 NRAS Mutation \| BRAF Wild-type \| NRAS Wild-type	20	trametinib+GSK2141795 (BRAFWT NRASWT patients)		不佳	2018-01-01
NCT01902173 (SWOG S1221, ASCO 12017 \| ASCO 22017) 人工标引	临床1期	BRAF突变实体瘤 BRAF V600 mutant	19	dabrafenib+GSK2141795	(壓製鑰糧製憲蓋鬱襯積) = At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash 憲醖選憲願襯廠獵鹽遞 (齋網積廠簾觸構鹹築鹽 )	积极	2017-06-05
NCT01902173 (SWOG S1221, ASCO 12017 \| ASCO 22017) 人工标引	临床1期	BRAF突变实体瘤 BRAF V600 mutant	19	dabrafenib+trametinib+GSK2141795		积极	2017-06-05
SGO2016	N/A	复发性子宫内膜癌	-	Trametinib 1.5 mg + GSK2141795 25 mg	窪鬱蓋鬱壓範鏇製構願(遞襯簾艱繭壓膚憲糧窪) = DL1 had 8 DLTs: hypertension (n = 2), mucositis (n = 2), rash (n = 2), dehydration (n = 1), and acute kidney injury (n = 1). DL1 was deemed nontolerable, so a second dose level was explored (DL-1: trametinib 1.5 mg, GSK2141795 25 mg). No DLTs were seen at DL-1. 糧憲憲餘選願醖鹹餘遞 (衊構願製遞壓艱夢簾壓 ) 更多	-	2016-06-01