In Vivo Absorption, Metabolism, Excretion (AME) Clinical Study of [14C]Afuresertib in Healthy Chinese Male Adults - Human Mass Balance and Biotransformation Study of [14C]Afuresertib

This study adopts a single-center, single-dose, non-randomized, open-label design with a proposed enrollment of 6-10 healthy male subjects. After a single oral dose of approximately 125 mg/150 µCi [14C]Afuresertib tablets, blood, urine and fecal specimens are collected from each subject at defined time points/periods during the trial, and PK parameters, recovery, and excretion routes of [14C]Afuresertib in plasma are calculated by measuring the total radioactivity. The main metabolic and elimination pathways and characteristics of Afuresertib in human, as well as circulating metabolites with close to or higher than 10% of plasma total radioactivity exposure, are also identified by plasma, urine, and fecal radioactive metabolite profiles and major metabolite structure.

开始日期2022-08-06

申办/合作机构

来凯医药科技（上海）有限公司初创企业

CTR20221613

/ Completed临床1期

[14C]Afuresertib 在中国成年男性健康受试者体内吸收、代谢和排泄临床试验-[14C]Afuresertib 人体物质平衡及生物转化研究

主要研究目的：1. 定量分析男性健康受试者口服[14C]Afuresertib 后排泄物中的总放射性，获得人体放射性排泄率数据和主要排泄途径；2. 考察男性健康受试者单次口服[14C]Afuresertib 后全血和血浆中的分配情况和血浆中总放射性的药代动力学；3. 鉴定男性健康受试者口服[14C]Afuresertib 后人体内的主要代谢产物，确定主要生物转化途径和主要代谢产物（接近或高于10%总放射性AUC）；4. 采用已验证的HPLC-MS/MS 方法定量分析血浆中Afuresertib及其代谢产物（如适用）的浓度，获得血浆中Afuresertib 及其代谢产物（如适用）的药代动力学参数。次要研究目的：观察[14C] Afuresertib 单次给药后男性健康受试者的安全性

开始日期2022-08-01

申办/合作机构

缔脉生物医药科技（上海）有限公司初创企业

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100 项与 Afuresertib 相关的临床结果

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100 项与 Afuresertib 相关的转化医学

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100 项与 Afuresertib 相关的专利（医药）

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

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.

2025-04-01·SLAS Discovery

Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids

Article

作者: Doroshow, James H ; Coussens, Nathan P ; Silvers, Thomas ; Morris, Joel ; Davoudi, Zahra ; Takebe, Naoko ; Teicher, Beverly A ; Said, Rabih ; Dexheimer, Thomas S ; Moscow, Jeffrey A

Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is a key contributor to cancer, making PI3K inhibitors a promising approach for targeted therapy. The selectivity of available inhibitors varies across different PI3K isoforms. Alpelisib and inavolisib are selective for the α-isoform, while duvelisib targets the δ- and γ-isoforms, and copanlisib is a pan-PI3K inhibitor, active against all isoforms. This study investigated the activity of these four PI3K inhibitors in combination with other targeted agents using multi-cell type tumor spheroids composed of 60% malignant cells, 25% endothelial cells, and 15% mesenchymal stem cells. Twenty-nine tumor spheroid models were evaluated, including twenty-six patient-derived cancer cell lines from the NCI Patient-Derived Models Repository and three established cell lines from the NCI-60 human tumor cell line panel. Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib.

2025-03-01·GYNECOLOGIC ONCOLOGY

An open-label randomized active-controlled phase II clinical study to assess the efficacy and safety of afuresertib plus paclitaxel versus paclitaxel in patients with platinum-resistant ovarian cancer (PROFECTA-II/GOG-3044)

Article

作者: Yue, Yong ; Buscema, Joseph ; Duan, Wei ; Finkelstein, Karen ; Liao, John B ; Willmott, Lyndsay ; Zweizig, Susan ; Wu, Lingying ; Wang, Xiaoyu ; Liu, Juan ; Zang, Rong-Yu ; Moroney, John W ; Campbell-Simms, Katie ; Herzog, Thomas J ; Yin, Rutie ; O'Malley, David M

OBJECTIVES:

To evaluate the efficacy and safety/tolerability of paclitaxel with and without the AKT inhibitor afuresertib in patients with platinum-resistant ovarian cancer (PROC).

METHODS:

This phase II open-label randomized trial (NCT04374630) enrolled 150 PROC patients to evaluate progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate, and duration of response. Eligible patients received 1-5 prior chemotherapies (≤1 post-PROC therapy). Biomarker analysis assessed PI3K/AKT/PTEN alterations, BRCA1/2-mutations, and phospho-AKT levels. Patients with prior AKT or mTOR inhibitor use were excluded. Randomization was stratified by country and prior use of bevacizumab and platinum-based treatment lines.

RESULTS:

In the intent-to-treat population, no statistically significant difference was observed in PFS between afuresertib+paclitaxel (A + P) vs. paclitaxel (Pac) alone (median PFS 4.3mos [95 % CI, 3.58-5.62] vs 4.1mos [95 % CI 2.63-5.36].

PFS HR:

0.7 (95 % CI, 0.50-1.10; P = 0.139). No statistically significant difference in median OS was observed either (11.2mos with A + P, 95 % CI, 8.38-13.77) vs. 13.1mos in Pac arm (95 % CI, 7.75-18) and HR = 1.2 (95 % CI, 0.77-1.81). In AKT mutation biomarker+ (IHC > 1) patients, the median PFS of A + P vs. Pac was 5.4mos vs. 2.9mos (HR = 0.4; 95 % CI, 0.12-1.00). Treatment-emergent adverse events (TEAEs) were consistent with AKT inhibitors, with serious TEAEs in 34.3 % (A + P) vs. 25.5 % (Pac), including diarrhea and gastrointestinal perforations.

CONCLUSIONS:

The addition of afuresertib to paclitaxel did not significantly improve PFS/OS in patients with PROC. However, exploratory biomarker findings suggest potential efficacy in phospho-AKT positive patients, warranting further investigation. The safety/tolerability profile of A + P was consistent with prior AKT-inhibitor studies.

项与 Afuresertib 相关的新闻（医药）

2025-04-18

·Insight数据库

国内首个！阿斯利康 AKT 抑制剂获批上市

4 月 18 日，NMPA 官网显示，阿斯利康 AKT 抑制剂卡匹色替片（Capivasertib）在国内获批上市，联合氟维司群用于转移性阶段至少接受过一种内分泌治疗后疾病进展，或在辅助治疗期间或完成辅助治疗后12个月内复发的激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性且伴有一种或多种PIK3CA/AKT1/PTEN改变的局部晚期或转移性乳腺癌成人患者。值得一提的是，Capivasertib 是国内首个获批上市的 AKT 抑制剂。截图来自：NMPA 官网Capivasertib 是一种强效、选择性泛 AKT 抑制剂，于 2023 年 11 月首次在美国获批上市，用于治疗 HR 阳性、HER2 阴性乳腺癌。2024 年 3 月和 6 月，该药又先后在日本和欧盟获批。截图来自：Insight 数据库2022 年 SABCS 大会上，阿斯利康公布了一项全球多中心、双盲、随机的 III 期 CAPItello-291 临床试验结果。该试验旨在评估 capivasertib 联合氟维司群对比安慰剂联合氟维司群治疗局部晚期（不可手术）或转移性 HR 阳性、HER2 阴性乳腺癌的安全性和有效性。该研究共纳入 708 名受试者，41% 的受试者患有 PIK3CA、AKT1 或 PTEN 突变。研究结果显示：在所有受试者中，Capivasertib+氟维司群和氟维司群+安慰剂组 mPFS 分别为 7.2 和 3.6 个月，与氟维司群+安慰剂组相比，Capivasertib+氟维司群组疾病进展或死亡风险降低 40%。ORR 为 22.9%（vs 12.2%）；在 PIK3CA/AKT1/PTEN 信号通路变异亚组中，Capivasertib+氟维司群和氟维司群+安慰剂组 mPFS 分别为 7.3 和 3.1 个月，与氟维司群+安慰剂组相比，Capivasertib+氟维司群组疾病进展或死亡风险降低 50%。ORR 为 28.8%（vs 9.7%）；在安全性方面，Capivasertib 联合氟维司群组最常见的任何级别的不良事件（AEs）是腹泻、恶心、皮疹（包括皮疹、斑疹、斑丘疹和瘙痒性皮疹）、疲劳和呕吐。5% 及以上的患者最常发生的 3 级或以上的 AE 是腹泻和皮疹。截图来自：Insight 数据库除了乳腺癌，Capivasertib 还在拓展不同的适应症，包括前列腺癌（III 期）、非小细胞肺癌（II 期）和血液肿瘤（I 期）。Insight 数据库显示，除了 Capivasertib 以外，全球还有 22 款 AKT 抑制剂进入临床阶段（仅统计积极状态），GSK 的 Afuresertib 和辉瑞的 Ipatasertib 进展最快，已经进入临床 III 期。截图来自：Insight 数据库（统计截止时间：2025 年 4 月 9 日）其中国产 AKT 抑制剂有 4 款，但都还处于临床早期阶段。截图来自：Insight 数据库（统计截止时间：2025 年 4 月 9 日）封面来源：企业 Logo免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：ccaiPR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn

上市批准临床3期临床结果临床2期

2025-03-26

·laekna.com

Laekna Announces First Visit for First Subject Completed in Phase I MAD Study of LAE102 for Obesity

- To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LAE102, administered subcutaneously, in 60 overweight/obese subjects - Robust SAD study data has established a solid foundation for the coming MAD Study - The Phase I clinical trial of LAE102 in the U.S is expected to commence in Q2 of 2025 March 26, 2025 — Laekna (2105.HK) announced that subject recruitment for the Phase I multiple ascending dose study of LAE102(monoclonal antibody against ActRIIA) for the treatment of obesity (the MAD study) has commenced. The first visit for the first subject has been completed. The MAD Study is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LAE102, administered subcutaneously, in 60 overweight/obese subjects. Dr. Chris Lu, Chairman of Laekna, said: " The positive outcomes of the SAD Study of LAE102 have established a solid foundation for the Phase I MAD study. The data demonstrated an encouraging safety and tolerability profile. Robust target engagement and expected pharmacodynamic biomarker changes have been observed.” He stated that the detailed results of the SAD study will be presented at an international scientific conference this year. Phase I clinical trial of LAE102 in the U.S is expected to commence in the second quarter of 2025. LAE102 is Laekna’s internally discovered monoclonal antibody selectively targeting ActRIIA, a receptor that plays an important role in muscle regeneration and lipid metabolism. In the pre-clinical models, LAE102 has been shown to increase lean mass and decrease fat mass. In combination with GLP1R agonist, LAE102 can further reduce fat mass and significantly regain the lean mass loss induced by GLP1R agonist. This positions LAE102 as a promising drug candidate for achieving quality weight control. In November 2024, Laekna entered into a clinical collaboration agreement with Eli Lilly and Company (NYSE: LLY) to support and accelerate global clinical development of LAE102 for the treatment of obesity. Laekna team has accumulated tremendous experience and extensive knowhow in the specific field of targeting ActRII receptors and is developing, in addition to LAE102, more drug candidates to maximize the value of the target. LAE103 is an ActRIIB-selective antibody and LAE123 is a dual inhibitor against ActRIIA/IIB. Both are our internally discovered antibodies for muscle and other disease indications and target to submit IND applications in 2025. - End – About LAE102 LAE102 is an internally discovered monoclonal antibody selectively targeting ActRIIA, a receptor that plays an important role in muscle regeneration and lipid metabolism. In the pre-clinical models, LAE102 has been shown to increase lean mass and decrease fat mass. In combination with GLP1R agonist, LAE102 can further reduce fat mass and significantly regain the lean mass loss induced by GLP1R agonist. This positions LAE102 as a promising drug candidate for achieving quality weight control. Contact Us IR ir@laekna.com Media communication@laekna.com Corporate and Business Development BD@laekna.com About Laekna Stock Code: 2105.HK Founded in 2016, Laekna is a science-driven, clinical-stage biotechnology company committed to bringing novel therapeutics to patients with metabolic diseases, cancer and liver fibrosis around the world. As of December 31, 2024, Laekna has initiated seven clinical trials for LAE102, LAE002 (afuresertib), LAE001 and LAE005 to address unmet medical needs in obesity and cancers. LAE102 is our internally discovered antibody against ActRIIA. Blocking Activin-ActRII pathway could promote muscle regeneration and decrease fat mass, this positions LAE102 as a promising drug candidate for achieving quality weight control. We’ve obtained IND approvals from the FDA and the CDE for LAE102 in obesity indication and are advancing the Phase I clinical trial in China. In November 2024, Laekna entered into a clinical collaboration agreement with Eli Lilly and Company to support and accelerate global clinical development of LAE102 for the treatment of obesity. Laekna team has accumulated tremendous experiences and deep know-how in the specific field of targeting ActRII receptors and is developing more drug candidates (LAE103 and LAE123), in addition to LAE102, to maximize the value of the target. LAE103 is an ActRIIB-selective antibody and LAE123 is a dual inhibitor against ActRIIA/IIB. Both are our internally discovered antibodies for muscle and other disease indications. In the cancer area, Laekna has built a comprehensive portfolio of drug candidates including LAE002(afuresertib), LAE001 and other seven pre-clinical drug candidates. LAE002 (afuresertib) is a potent AKT inhibitor that inhibits all three AKT isoforms (AKT1, AKT2 and AKT3) as well as one of the only two AKT inhibitors in late-stage development for breast and prostate cancer globally. Laekna has commenced the Phase III clinical trial (AFFIRM-205) for LAE002 in patients with HR+/HER2- breast cancer and the study recruitment is on track. Laekna, Inc. (2105.HK) was listed on the Main Board of The Stock Exchange of Hong Kong Limited (the “Hong Kong Stock Exchange”) on June 29, 2023. For more information, please visit: https://www.laekna.com/ or https://www.linkedin.com/company/74110713/ Forward-Looking Statements This press release may contain certain “forward-looking statements” which are not historical facts, but instead are predictions about future events based on Laekna’s current beliefs, assumptions and expectations, commonly identified by words such as "would", "may", "expects", "believes", "plans", "intends", "projects" and other terms with similar meaning. Although we believe that our predictions are reasonable, future events are inherently uncertain and our actual future results or performance may be materially different from what we expect. Accordingly, you are strongly cautioned that reliance on any forward-looking statements is subject to significant known and unknown risks and uncertainties. All forward-looking statements contained herein are qualified by reference to the cautionary statements set forth in this section. All information provided in this press release is as of the date of this press release and are based on assumptions that we believe to be reasonable as of this date, and we do not undertake any obligation to update any forward-looking statement, except as required under applicable law.

临床1期临床3期临床申请

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

100 项与 Afuresertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10381	-	-	DB11648

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
HR阳性/HER2阴性乳腺癌	临床3期	美国	来凯医药	2022-02-18
HR阳性/HER2阴性乳腺癌	临床3期	中国	来凯医药	2022-02-18
食管癌	临床2期	中国	来凯医药科技（上海）有限公司初创企业	2022-06-30
胆管癌	临床2期	中国	来凯医药科技（上海）有限公司初创企业	2022-06-22
胆管癌	临床2期	中国	Halo Pharmaceutical, Inc.	2022-06-22
子宫内膜癌	临床2期	中国	Halo Pharmaceutical, Inc.	2022-06-22
子宫内膜癌	临床2期	中国	来凯医药科技（上海）有限公司初创企业	2022-06-22
胃食管交界处腺癌	临床2期	中国	来凯医药科技（上海）有限公司初创企业	2022-06-22
胃食管交界处腺癌	临床2期	中国	Halo Pharmaceutical, Inc.	2022-06-22
非小细胞肺癌	临床2期	中国	Halo Pharmaceutical, Inc.	2022-06-22

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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


NCT05383482 (IGCS2024) 人工标引	临床1/2期	实体瘤 \| 子宫内膜癌 \| 宫颈癌	18	Afuresertib + Sintilimab + Nab-paclitaxel	構鏇製選憲範廠顧網遞(遞製網衊築鏇築齋廠齋) = 鏇艱醖鏇鹽鏇齋築膚壓餘簾鬱觸廠憲糧醖糧積 (窪壓鏇蓋襯鬱齋觸醖餘, 31.6 ~ 86.1) 更多	积极	2024-10-16
NCT04851613 (NEWS) 人工标引	临床1期	HR阳性/HER2阴性乳腺癌 Hormone Receptor Positive \| HER2 Negative	18	LAE002 (afuresertib) plus fulvestrant (PIK3CA/AKT1/PTEN alteration)	繭蓋獵蓋繭廠醖夢築遞(製構繭製製選艱積製選) = 選積壓糧範窪夢糧窪艱簾繭淵繭獵膚餘憲獵齋 (獵網構製簾鏇夢醖觸廠 ) 更多	积极	2024-09-19
NCT04851613 (ESMO2024) 人工标引	临床1期	HR阳性/HER2阴性乳腺癌 HER2 Negative \| Hormone Receptor Positive ... 更多	31	Afuresertib plus fulvestrant	製醖選構淵憲積鏇鏇製(鑰醖構襯簾簾鹽遞鏇窪) = 蓋憲積艱膚獵衊膚顧艱齋夢積選遞夢觸築鹹鑰 (鏇選艱網夢構網願衊憲 ) 更多	积极	2024-09-16
NCT04851613 (ESMO2024) 人工标引	临床1期		31	afuresertib (PIK3CA/AKT1/PTEN-altered subjects)	製醖選構淵憲積鏇鏇製(鑰醖構襯簾簾鹽遞鏇窪) = 築繭獵網淵憲鬱繭艱齋齋夢積選遞夢觸築鹹鑰 (鏇選艱網夢構網願衊憲 ) 更多	积极	2024-09-16
NCT04374630 (PROFECTA II, Corporate Publications) 人工标引	临床2期	铂耐药性卵巢癌	150	Afuresertib+Paclitaxel	衊壓齋壓膚範選夢衊積(顧蓋鬱構鹹積膚製窪夢): HR = 0.744 (95% CI, 0.502 ~ 1.102) 未达到	不佳	2024-01-28
NCT04374630 (PROFECTA II, Corporate Publications) 人工标引	临床2期	铂耐药性卵巢癌	150	Paclitaxel		不佳	2024-01-28
NCT04060394 (ESMO 12023 \| ESMO 22023) 人工标引	临床1/2期	转移性去势抵抗性前列腺癌	40	LAE001+prednisone+ afuresertib	鏇衊鏇齋夢鏇襯餘網繭(鹽網夢觸壓廠遞繭蓋糧) = thrombocytopenia (7.5%), anaemia (5.0%), hyperglycaemia (5.0%), hyponatraemia (5.0%), and hypertension (5.0%). SAEs were reported in 9 patients (22.5%), 5 (12.5%) were assessed as related to study treatment 築製鬱製獵網廠顧淵艱 (積壓顧鹹觸構膚簾簾顧 )	积极	2023-10-22
NCT01531894 (CTgov)	临床2期	实体瘤 \| 血液肿瘤	11	GSK2110183 (afuresertib)	鏇膚繭壓鏇築憲築範遞 = 顧繭廠鏇積鑰製廠膚鹹簾廠鑰糧襯糧鏇鑰遞衊 (襯淵簾築製鏇艱艱艱鑰, 獵膚蓋襯淵獵網選醖鹹 ~ 壓窪築製積壓廠淵窪艱)	-	2019-07-09
NCT01653912 (Pubmed \| Clin Cancer Res)	临床1/2期	复发性铂耐药性卵巢癌	59	Afuresertib	衊製願艱遞鹽網糧繭構(蓋窪膚觸鹽憲構膚網範) = 糧膚簾鑰製觸鹹選願願襯齋積餘製廠鹹艱餘鬱 (顧築膚積餘蓋鏇鹹願鹽, 15.9 ~ 52.4) 更多	-	2019-03-01
NCT01653912 (Pubmed \| Clin Cancer Res)	临床1/2期	复发性铂耐药性卵巢癌	59	Carboplatin and Paclitaxel	衊製願艱遞鹽網糧繭構(蓋窪膚觸鹽憲構膚網範) = 糧衊鬱顧積築獵鬱觸膚襯齋積餘製廠鹹艱餘鬱 (顧築膚積餘蓋鏇鹹願鹽, 31.3 ~ 72.2)	-	2019-03-01
NCT01653912 (CTgov)	临床1/2期	铂耐药性卵巢癌 \| 复发性铂耐药性卵巢癌	59	GSK2110183 (Phase 1 (Dose Escalation): GSK2110183)	鑰壓製襯廠願夢選鹽蓋 = 蓋獵膚鑰鹹觸網衊憲艱蓋鑰夢衊顧鹹顧淵範淵 (窪夢顧膚醖遞鑰鬱網積, 淵獵襯膚鬱築蓋糧艱構 ~ 艱壓築衊壓築鑰積鑰醖) 更多	-	2018-04-02
NCT01653912 (CTgov)	临床1/2期	铂耐药性卵巢癌 \| 复发性铂耐药性卵巢癌	59	GSK2110183 (Phase 2 (Treatment Group): GSK2110183)	鏇積鏇憲選獵選淵遞糧 = 糧齋糧築憲膚鏇鬱鏇鏇醖繭願醖鹽繭鑰遞衊齋 (夢襯蓋製顧糧獵蓋鹹醖, 觸淵積範鏇壓鬱膚願築 ~ 憲窪蓋鹽廠淵膚糧獵齋) 更多	-	2018-04-02
NCT01653912 (ASCO2016)	临床1/2期	复发性卵巢癌	59	Afuresertib + Paclitaxel + Carboplatin	鏇糧繭壓鏇艱糧窪鹹壓(窪顧簾憲襯顧齋窪襯艱) = G3/4 AEs included diarrhea (20%), fatigue (10%), rash (10%), vomiting (7%), and nausea (3%) 廠壓鹽觸糧廠獵膚齋醖 (遞鑰憲鹹顧積衊廠膚繭 )	积极	2016-05-20
NCT01476137 (Pubmed \| Cancer Chemother Pharmacol) 人工标引	临床1期	实体瘤 \| 多发性骨髓瘤	20	trametinib+afuresertib	獵鏇憲衊艱網淵夢願積(鑰願襯糧衊繭壓鹹鏇築) = Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously) 鬱膚膚鹹鹽壓艱襯繭選 (夢憲鹹齋獵壓窪鑰廠選 ) 更多	不佳	2015-01-01