更新于：2024-11-21

CEP-11981

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

2,5,6,11,12,13-Hexahydro-2-methyl-11-(2-methylpropyl)-8-(2-pyrimidinylamino)-4H-indazolo[5,4-c]pyrrolo[3,4-c]carbazol-4-one mono(4-methylbenzenesulfonate)

+ [4]

靶点

Tie-2 x VEGFR2

作用机制

Tie-2拮抗剂(泰克酪氨酸激酶拮抗剂)、VEGFR2拮抗剂(血管内皮细胞生长因子受体2拮抗剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [2]

在研适应症

腺鳞癌胃肠胰神经内分泌肿瘤胃肠道神经内分泌肿瘤+ [6]

非在研适应症

转移性肾细胞癌

原研机构

Sanofi

在研机构

Rogel Cancer Center: University of Michigan

SanofiEsanik Therapeutics, Inc.

+ [1]

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构

分子式C28H27N7O

InChIKeyAEULIVPVIDOLIN-UHFFFAOYSA-N

CAS号856691-93-5

关联

项与 CEP-11981 相关的临床试验

NCT05988918 / Recruiting临床2期IIT

A Phase II Multicenter Trial of ESK981 in Patients With Select Solid Tumors

This protocol will enroll patients with pancreatic adenocarcinoma and adenosquamous carcinoma (Cohort 1), gastrointestinal/pancreatic neuroendocrine neoplasms with Ki-67 > 20% (Cohort 2) and neuroendocrine prostate carcinoma (Cohort 3)). Each cohort will have its own interim analysis after enrollment of 10 patients.
Subjects will be given a one-month (28 day) supply of study drug (ESK981). Subjects will be instructed to take 4 capsules, with or without food, once per day for 5 consecutive calendar days, then take a drug holiday for 2 consecutive days before repeating the 5 days on-2 days off cycle in sets of 4 weeks or 28 calendar days. Subjects will be asked to keep a pill diary noting the date they take their study drug.

开始日期2024-04-19

申办/合作机构

Rogel Cancer Center: University of Michigan

NCT04159896 / Terminated临床2期IIT

Phase II Multi-Center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Castrate Resistant Prostate Cancer

This phase II trial studies the side effects of ESK981 and nivolumab and to see how well they work for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). ESK981 is an investigational drug that targets several important pathways that are believed to play a role in the spread of cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if giving ESK981 and nivolumab together works better in treating metastatic castration resistant prostate cancer compared to usual treatments.

开始日期2019-11-13

申办/合作机构

Barbara Ann Karmanos Cancer Institute

[+1]

NCT03562507 / Terminated临床2期IIT

ERICA: Phase 2 Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma

The objective of the trial is to determine the clinical efficacy of ESK981 in combination with nivolumab therapy in patients with metastatic renal cell carcinoma (RCC).

开始日期2019-04-11

申办/合作机构

Rogel Cancer Center: University of Michigan

100 项与 CEP-11981 相关的临床结果

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100 项与 CEP-11981 相关的转化医学

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100 项与 CEP-11981 相关的专利（医药）

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项与 CEP-11981 相关的文献（医药）

2020-04-01·Journal of Nuclear Medicine1区 · 医学

PET Imaging of Pancreatic Dopamine D₂ and D₃ Receptor Density with ¹¹C-(+)-PHNO in Type 1 Diabetes

1区 · 医学

Article

作者: Sanchez-Rangel, Elizabeth ; Bini, Jason ; Matuskey, David ; Huang, Yiyun ; Harris, Paul E ; Cline, Gary W ; Nabulsi, Nabeel ; Gallezot, Jean-Dominique ; Ropchan, Jim ; Najafzadeh, Soheila ; Naganawa, Mika ; Lim, Keunpoong ; Sherwin, Robert S ; Shirali, Anupama ; Carson, Richard E ; Herold, Kevan C

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D₂ and D₃ receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (¹¹C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R ² = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R ² = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R ² = 0.57, P = 0.05), nor did mean baseline proinsulin (R ² = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D₃ receptor and dopamine D₂ receptor in HCs. No colocalization of the dopamine D₃ receptor or dopamine D₂ receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D₃ receptor, dopamine D₂ receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D₃ receptor and dopamine D₂ receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for ¹¹C-(+)-PHNO, a dopamine D₃ receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

2018-12-19·ACS Chemical Neuroscience3区 · 医学

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B

3区 · 医学

Article

作者: Koeppe, Robert A. ; Brooks, Allen F. ; Kilbourn, Michael R. ; Pham, Jonathan M. ; Mufarreh, Anthony J. ; Shao, Xia ; Scott, Peter J. H. ; Drake, Lindsey R.

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[¹¹C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([¹¹C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [¹¹C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [¹¹C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [¹¹C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

2014-12-01·Investigational New Drugs3区 · 医学

An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer

3区 · 医学

Article

作者: Michael Carducci ; Peter Brown ; Roberto Pili ; Herbert Hurwitz

SummaryBackground This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

项与 CEP-11981 相关的新闻（医药）

2023-01-07

·生物制品圈

Nature Review | 抑制磷酸肌醇激酶，有望治愈所有疾病！

脂质磷酸肌醇是细胞各种生命活动的主要调节剂，由磷酸肌醇激酶严格调控产生。目前主要集中在I类磷酸肌醇3-激酶 (PI3K) 的药物治疗上，但近年来已经揭示了靶向几乎所有人类疾病中磷酸肌醇激酶的可能性，包括癌症、免疫缺陷、病毒感染和神经退行性疾病，开发更多磷酸肌醇激酶的强效和选择性抑制剂成为自然趋势。磷酸肌醇激酶可大致分为三个家族：第一个家族包含所有类别的磷酸肌醇3-激酶（PI3K）和III型PI4K，第二个家族包含PIP激酶，最后一个家族包含II型PI4K（图 1）。本文将对这三个家族的前沿进展进行详细分析。图1 磷酸肌醇和产生它们的磷酸肌醇激酶I类PI3K抑制剂磷酸肌醇激酶是多种人类疾病的治疗靶点，包括癌症、病毒感染、神经退行性疾病、发育障碍、糖尿病和炎症性疾病。目前，有许多I类PI3K抑制剂在临床上被批准用于治疗多种癌症。I类磷酸肌醇3激酶(PI3K)产生磷脂酰肌醇3,4,5-三磷酸(PIP3)，是细胞生长、代谢和免疫功能的主要调节剂。PI3K通路是癌症中突变最频繁的通路，PI3K的体细胞突变是多种人类癌症、原发性免疫缺陷、发育障碍和过度生长综合征的致病因素。PI3K 抑制剂的研发将为其他磷酸肌醇激酶抑制剂的设计提供信息。表1 I类PI3K抑制剂进展情况I 类PI3K以外的磷酸肌醇激酶抑制剂2.1 PIP激酶演化家族2.1.1 PIKfyve● 结构PIKfyve是真核生物中唯一催化从磷脂酰肌醇3-磷酸(PI3P)生产磷脂酰肌醇3,5-二磷酸(PI(3,5)P2)的蛋白质。除了脂质激酶活性外，PIKfyve还具有蛋白激酶活性，并受抑制性自磷酸化调节。PIKfyve复合体在离子稳态，内吞途径的内体运输、细胞迁移和溶酶体功能中发挥作用。对小鼠突变体和敲除模型以及患者临床突变的研究揭示了PIKfyve复合体所有成员在中枢和周围神经系统中的关键作用。图 2：PIKfyve 的结构-功能、抑制和治疗靶向● 药理抑制剂PIKfyve抑制剂通过破坏内溶酶体运输来阻断病毒进入宿主细胞质，从而显示出作为抑制病毒感染靶点的前景。能够改善神经退行性疾病，抑制病毒感染和癌症。目前已开发出多种PIKfyve抑制剂。大部分PIKfyve抑制剂还处于临床前阶段，如YM201636，MF4，APY0201，WX8，NDF和MOMIPP。第一个被发现的强效和选择性PIKfyve抑制剂YM201636源于针对I类PI3K的药物发现，它对PIKfyve非常有效，选择性是I类PI3Kp110α的100倍。PIKfyve抑制剂Apilimod和ESK981正在进行针对癌症和病毒感染的临床试验。PIKfyve抑制剂YM201636和Apilimod都阻断了帕金森病体外模型HEK293细胞中α-突触核蛋白的单体聚集。表2 PIKfyve抑制剂总结2.1.2 PI4P5Ks和PI5P4Ks● 结构PI(4,5)P2是哺乳动物细胞中最丰富的双磷酸化磷酸肌醇，而且还是基本癌症和代谢激酶PI3K的底物。负责产生PI(4,5)P2的激酶被分为两个亚家族，即I型和II型激酶。在哺乳动物中，I型PI4P5K家族由三种亚型（PI4P5Kα、PI4P5Kβ和PI4P5Kγ）组成，也存在三种哺乳动物II型PI5P4K亚型（PI5P4Kα、PI5P4Kβ和PI5P4Kγ）。图 3：PI4P5K 和 PI5P4K 的结构-功能和抑制● PI4P5Ks的药理学抑制剂迄今为止，已经报道了有限数量的有效和特异性PI4P5K抑制剂，并且仍处于临床前开发的早期阶段，它们被报道抑制癌症和炎症性疾病（表3）。其中最好的是ISA-2011B，它以高亲和力结合PI4P5Kα并在多种模型中抑制其蛋白质表达和癌症生长以及抑制炎症，但它具有显着的脱靶效应，进一步优化ISA-2011B，或开发另一种对PI4P5Kα具有更高选择性的基团，将是推进PI4P5Kα抑制剂超越临床前研究的必要条件。●PI5P4Ks的药理学抑制剂PI5P4K已成为p53无效肿瘤中有吸引力的药物靶标，并被认为是代谢的关键调节剂。临床前研究正在探索早期阶段的小分子抑制剂，包括泛PI5P4K抑制剂和亚型特异性PI5P4K抑制剂（表3），它们表现出抑制糖尿病，免疫性疾病，神经退行性疾病和抗癌效果，但目前尚未进入临床阶段。表3 PI4P5Ks和PI5P4Ks抑制剂总结2.2 PI3K−III型PI4K进化家族2.2.1 PI4KA和PI4KB● 结构有四种哺乳动物磷脂酰肌醇4-激酶(PI4K)，由II型（PI4KIIα和PI4KIIβ）和III型（PI4KIIIα和PI4KIIIβ，）组成，它们一起从磷脂酰肌醇中产生PI4P。PI4P在多种细胞器中介导了蛋白质的膜募集、整合膜蛋白活性的调节和细胞器之间的脂质转运。PI4KA和PI4KB蛋白具有与PI3Ks进化相关的同源螺旋和脂质激酶结构域（图4a、b）。然而，这两种蛋白质通过一组独特的蛋白质结合分子和翻译后修饰具有不同的调节模式。图 4：PI4KA 和 PI4KB 的结构-功能、抑制和治疗靶向● PI4KA的药理学抑制剂PI4KA在HCV感染中的关键作用促进有效和特异性PI4KA抑制剂的开发。PI4KB抑制剂可预防病毒感染，寄生虫感染，PI4KA和PI4KB抑制剂具有抗癌作用。表 4 III型PI4K和II、III类PI3K的抑制剂总结2.3 II类PI3K● 结构II类PI3K，也称为PI3KC2，存在α、β和γ三种亚型。PI3KC2s催化PI和PI4P的3-OH磷酸化；因此，它们似乎既是用于PI3P合成的III类PI3K的替代品，也是I类PI3K和5-OH磷酸酶介导的PI(3,4)P2生产的替代品。研究最深入的II类亚型是PI3KC2α，它在发育中起着至关重要的作用，PI3KC2α生成的PI(3,4)P2作为内吞作用的关键驱动因素。PI3KC2β中激酶死亡突变的纯合小鼠表现出葡萄糖耐量增强。图 5：II类PI3K的结构-功能、抑制和治疗靶向● 药理抑制剂PI3KC2的初始抑制剂是从I类PI3K抑制剂PIK-90的衍生物开发的，得到4-氨基烟酰胺衍生物MIPS-19416，它显示出对PI3KC2α和PI3KC2β的效力。高通量筛选和迭代药物化学优化的结合促成了高选择性PI3KC2α抑制剂(PITCOIN)的开发。PI3KC2α抑制剂能够抗血栓形成，抑制肺癌和黑色素瘤模型的血管生成和肿瘤生长。表5 II 类 PI3K抑制剂总结 2.4 III类PI3K：VPS34● 结构III类PI3K，VPS34是真核生物中的原始PI3K酶。它在体外和体内专门催化PI产生PI3P（图1），并且被发现为两种不同的四聚体复合物，即复合物I和复合物II。这两种复合物具有本质上相同的激活机制：通过每个复合物独有的一系列相互作用，将VPS34域从受抑制的构象中释放出来。这两个复合物在功能上是不同的，复合物I启动巨自噬，而复合物II调控内吞途径的流量。图 6：III 类 PI3K 的结构-功能、抑制和治疗靶向● III类PI3K的药理学二十多年前发现的自噬抑制剂3-甲基腺嘌呤(3-MA)可抑制VPS34，但选择性极差。最近，已经开发出几种有效且高度选择性的VPS34抑制剂用于临床前研究。最近的临床前研究也表明这些化合物可有效治疗癌症。表6 III类PI3K抑制剂总结展望许多磷酸肌醇激酶与各种血液学、神经学和传染病以及各种癌症有关。它们已被证明适合小分子抑制剂的开发，预示着作为真正治疗靶点的巨大潜力。已经为大多数PI3K超家族以及PIKfyve开发了高效和选择性抑制剂；这些都处于高级临床前研究阶段，甚至进入临床试验阶段，针对PI4P5Ks和PI5P4Ks以及II型PI4Ks也开发了有前景的工具化合物。参考资料：1. Burke, J.E., Triscott, J., Emerling, B.M. et al. Beyond PI3Ks: targeting phosphoinositide kinases in disease. Nat Rev Drug Discov (2022). https://doi.org/10.1038/s41573-022-00582-52. 智慧芽数据库https://synapse.zhihuiya.com/3 摄图.新视界

临床结果

100 项与 CEP-11981 相关的药物交易

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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
腺鳞癌	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
胃肠胰神经内分泌肿瘤	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
胃肠道神经内分泌肿瘤	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
胰腺神经内分泌肿瘤	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
胰腺腺癌	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
神经内分泌前列腺癌	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
高分化胰腺内分泌肿瘤	临床2期	美国	Rogel Cancer Center: University of Michigan	2024-04-19
前列腺癌	临床2期	-	Sanofi	-
前列腺癌	临床2期	-	Teva Pharmaceutical Industries Ltd.	-
转移性肾细胞癌	临床1期	美国	Rogel Cancer Center: University of Michigan	2019-04-11

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临床结果

适应症

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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


NCT04159896 (Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab, Pubmed \| Invest New Drugs)	临床2期	转移性去势抵抗性前列腺癌 prostate-specific antigen \| AR amplification	10	ESK981	(糧願鹽壓壓窪鹹獵襯範) = 製範繭繭醖壓膚鏇簾鬱簾壓壓繭積鹹範夢遞衊 (淵壓淵鹽醖獵襯艱鹹蓋, 1.8 ~ 22.4) 更多	不佳	2024-11-06
NCT03456804 (Pubmed \| Invest New Drugs) 人工标引	临床2期	去势抵抗性前列腺癌 androgen receptor-positive (AR +)	13	ESK981 160 mg	(構淵艱範鑰構鑰醖遞鬱) = 蓋襯觸選衊鏇廠衊鏇窪艱齋構願構衊壓觸鏇繭 (夢積鹽願觸築淵獵膚襯, 0.4 ~ 33.3) 更多	不佳	2024-09-03
NCT04159896 (Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab, CTgov)	临床2期	去势抵抗性前列腺癌 \| 转移性前列腺癌 \| 转移性去势抵抗性前列腺癌	10	Nivolumab+Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981	齋蓋夢觸鏇蓋構艱壓衊(顧壓顧鬱艱鬱網遞蓋顧) = 淵願壓壓範顧範衊遞願鏇選夢選醖構艱顧襯製 (鏇簾餘獵網積網鬱製憲, 淵廠衊顧範網鬱積蓋選 ~ 構糧網壓鬱鏇壓繭艱餘) 更多	-	2024-07-16
NCT03456804 (Phase II trial of multi-kinase inhibitor ESK981, CTgov)	临床2期	涎腺多形性腺瘤 \| 去势抵抗性前列腺癌 \| 转移性前列腺癌	13	ESK981	艱壓獵襯糧顧選艱簾積(積範齋簾憲觸鹹選繭糧) = 選壓網餘壓憲繭膚觸鑰夢憲餘獵獵衊繭構積製 (築廠齋鑰遞獵艱觸艱鏇, 淵憲築觸構廠糧鏇遞壓 ~ 齋夢醖壓夢積繭鑰鹹築) 更多	-	2023-07-14