LCL-161(LCL-161) - 药物靶点：IAP_专利_临床

概要

基本信息

药物类型

小分子化药

别名

LCL 161、NVP-LCL161

靶点

IAP

作用机制

Inhibitors of apoptosis (IAP) protein family inhibitors

治疗领域

肿瘤皮肤和肌肉骨骼疾病内分泌与代谢疾病+ [7]

在研适应症-

非在研适应症

晚期恶性实体瘤结直肠癌非小细胞肺癌+ [6]

原研机构

Novartis Pharma AG

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.US Oncology Research LLC

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C26H33FN4O3S

InChIKeyUFPFGVNKHCLJJO-SSKFGXFMSA-N

CAS号1005342-46-0

关联

8

项与 LCL-161 相关的临床试验

NCT03111992 / Completed临床1期

Phase I/Ib, Multi-center, Open-label, Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Relapsed and/or Refractory Multiple Myeloma

The purpose of this study is to assess the safety, tolerability, and identify the recommended doses of single agent CJM112, and of CJM112 or LCL161 in combination with PDR001, in patients with relapsed and/or refractory multiple myeloma.

开始日期2017-12-18

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT02890069 / Completed临床1期

Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With LCL161, Everolimus (RAD001) or Panobinostat (LBH589)

The purpose of this study was to combine the PDR001 checkpoint inhibitor with several agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.

开始日期2016-10-14

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT02649673 / Terminated临床1期

Phase Ib Dose-Escalation Study of LCL161 in Combination With Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer (SCLC) and Select Gynecologic Malignancies

This trial will investigate the combination of two anti-cancer agents to treat patients with relapsed/refractory small cell lung cancer (SCLC) and ovarian cancers. Oral topotecan has US FDA approval for treating select gynecological cancers and SCLC. LCL161 is an investigational product that has been shown in clinical trials to work together with other anti-cancer agents. In this trial, investigators will determine the optimal dose of LCL161 and topotecan to administer to patients with relapsed/refractory SCLC and ovarian cancers, and examine the safety profile of the drug combination.

开始日期2016-03-23

申办/合作机构

SCRI Development Innovations, LLC

[+1]

100 项与 LCL-161 相关的临床结果

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100 项与 LCL-161 相关的转化医学

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100 项与 LCL-161 相关的专利（医药）

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94

项与 LCL-161 相关的文献（医药）

2024-09-01·Heliyon

Copper metabolism–related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer

Article

作者: Han, Chaojie ; Xu, Shoufang ; Jiang, Feiyu ; Han, Yetao ; Liu, Zhiwei ; Li, Yunsen ; Wang, Yingjian ; Feng, Zhangyang ; Hu, Mengsi

Objectives:

To comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism.

Methods:

Copper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays.

Results:

Four copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration.

Conclusion:

The identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

2024-05-20·CURRENT MEDICINAL CHEMISTRY

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer

Article

作者: Zheng, Xiang ; Rao, Guo-Wu ; Zhao, Jiang-Ting ; Zheng, Quan

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

2024-03-01·Journal of cellular and molecular medicine

Identification of the novel markers of PPAR signalling affecting immune microenvironment and immunotherapy response of lung adenocarcinoma patients

Article

作者: Zhu, Qi ; Wang, Jianjie ; Li, Quan ; Zhou, Meilan ; Ren, Xin ; Li, Yuehua ; Zhang, Zhengbin ; Zhang, Wei ; Liu, Junhui ; Wu, Gang

Abstract:

Peroxisome proliferator‐activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR‐related genes in lung adenocarcinoma (LUAD). Open‐access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR‐associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR‐related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA‐LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high‐risk individuals. Further, we observed that these high‐risk patients exhibited heightened genomic instability. Additionally, compared to the low‐risk cohort, high‐risk patients demonstrated diminished immune components and function. Intriguingly, high‐risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR‐related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.

1

项与 LCL-161 相关的新闻（医药）

2022-07-20

·CPhI制药在线

新药 | IAP抑制剂研究进展：xevinapant引发超10亿美元交易，亚盛医药领跑国内市场

点击关注，星标CPhI制药在线细胞凋亡是一种消灭不需要或异常细胞的重要程序性死亡方式，而抵抗细胞凋亡是癌症的经典标志之一。细胞凋亡抑制因子(IAP)家族是新发现的一类在结构上具有同源性的细胞凋亡抑制蛋白，是一类高度保守的独立于 Bcl-2 家族的内源性抑凋亡基因家族表达产物，通过与末端效应器caspase-3,7结合和干扰caspase-9的活性抑制凋亡。自1993年科学家在杆状病毒中首次发现IAP蛋白，目前已有8种IAPs蛋白家族成员被发现，即NAIP、c-IAP1、c-IAP2、XIAP、Survivin、Bruce、ILP-2和Livin。cIAP1、cIAP2和XIAP是IAP家族的主要成员，其中XIAP可以结合caspase-3、caspase-7、caspase-9等关键促凋亡节点，其他IAP家族蛋白成员则通过调控NF-κB信号通路中的某些关键蛋白的泛素化状态，实现对整个凋亡通路的调控。近年来，研究发现多种肿瘤中发生IAP失调，如肺癌、头颈部肿瘤、乳腺癌、消化道肿瘤、黑色素瘤和多发性骨髓瘤，且IAP蛋白的高表达促进了肿瘤发生和肿瘤转移。目前，IAP抑制剂已成为抗肿瘤药物开发的重要方向，但至今还没有以IAP靶点的药物获批上市。 IAP抑制剂可分为SMAC模拟物和非肽类小分子两类，其中SMAC模拟物可依据结合位点的数目分为单体和二聚体抑制剂，单体抑制剂（如LCL161、AT-406）能与XIAP、cIAP1、cIAP2结合，激活Caspase-9活性，解除IAP对Caspase的抑制作用；二聚体抑制剂（如APG-1387）可激活Caspase-3/7/9的活性，达到促进细胞凋亡的目的。2020年Blood 杂志上发表的一篇论文指出，包括birinapant、LCL-161在内的SMAC模拟物可作为CAR-T细胞杀伤能力增强剂。目前，在研IAP抑制剂多处于临床早期，其中xevinapant进展最快，目前正在处于关键3期临床研究TrilynX中，评估其联合含铂化疗和标准分割调强放疗，用于既往未经治疗的高危局部晚期头颈部鳞状细胞癌（LA SCCHN）患者的疗效和安全性。xevinapant是一种潜在"first-in-class"强效、口服IAP拮抗剂，曾被FDA授予突破性疗法认定，联合当前标准治疗、含铂化疗和标准分割调强放疗，用于既往未经治疗的LA SCCHN确诊患者。已公布的2期临床试验结果显示，xevinapant与放化疗联用，治疗18个月后54.2%的患者获得肿瘤局部控制，比对照组提高了约20个百分点,达到试验主要终点。2021年3月，德国默克与Debiopharm达成一项全球性许可协议，获得该药在全球范围内的开发和推广权益，交易价值近9亿欧元（11亿美元）。我国亚盛医药、正大天晴也积极布局IAP抑制剂领域。其中亚盛医药自主研发的APG-1387是我国首个进入临床试验阶段的IAP抑制剂，主要通过模拟内源性 SMAC分子降解IAPs来诱导和加速细胞凋亡的进程。一系列体内外研究表明，APG-1387单用以及与化疗药物或靶向治疗联用，能够有效抑制不同的异种移植瘤模型的肿瘤细胞生长。此外，APG-1387还被开发用以治疗乙肝。研究发现，单剂量每周注射一次发现 APG-1387能有效清除持续存在HBV动物体内的 HBsAg 和病毒 DNA。该药能降解肝脏 cIAPs，使HBV感染的肝细胞对免疫介导的细胞杀伤敏感，从而促进HBV特异性T细胞介导的DNA和抗原的清除。而且，在动物实验中，APG-1387与Birinapant 相比，显示出更好的疗效和安全性。整体来看，IAP抑制剂与化疗、放疗及免疫疗法联用是临床研究的重要探索方向，期待未来IAP抑制剂可以成为人类抗争疾病的新武器。智药研习社8月直播讲座报名速来投稿参与金笔奖征文，稿费丰厚！来源：CPhI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法放射疗法AACR会议突破性疗法First in Class

100 项与 LCL-161 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12085

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
三阴性乳腺癌	临床2期	美国	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	澳大利亚	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	巴西	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	捷克	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	德国	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	爱尔兰	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	意大利	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	俄罗斯	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	韩国	Novartis Pharmaceuticals Corp.	2012-08-01
三阴性乳腺癌	临床2期	西班牙	Novartis Pharmaceuticals Corp.	2012-08-01

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临床结果

适应症

分期

评价

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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


NCT01617668 (Pubmed) 人工标引	临床2期	三阴性乳腺癌 ER Negative \| PR Negative \| HER2 Negative	209	Paclitaxel+LCL 161	夢壓壓齋齋製蓋淵淵窪(鏇願顧壓窪醖簾齋鹽廠) = 鑰淵觸膚衊觸淵鹽艱蓋夢蓋蓋簾鏇夢膚淵糧鬱 (齋鏇壓簾獵夢願艱衊選 ) 更多	积极	2018-09-20
				Paclitaxel	夢壓壓齋齋製蓋淵淵窪(鏇願顧壓窪醖簾齋鹽廠) = 鹽窪鏇蓋餘構鹽顧獵餘夢蓋蓋簾鏇夢膚淵糧鬱 (齋鏇壓簾獵夢願艱衊選 ) 更多
NCT01617668 (ASCO2015)	临床2期	三阴性乳腺癌新辅助	209	LCL161 with paclitaxel	範選膚鏇醖簾壓構構艱(衊鑰餘艱蓋獵壓廠繭艱) = 襯鬱衊壓鏇窪選網遞鑰襯廠簾窪夢積淵鹽鏇憲 (簾遞齋艱繭齋獵憲積醖 )	-	2015-05-20
				Paclitaxel alone	範選膚鏇醖簾壓構構艱(衊鑰餘艱蓋獵壓廠繭艱) = 繭齋窪蓋淵鹽鹹願顧餘襯廠簾窪夢積淵鹽鏇憲 (簾遞齋艱繭齋獵憲積醖 )
AACR2010	临床1期	晚期癌症	27	LCL161	襯製範衊鏇築網願餘鬱(鑰夢憲膚繭壓選遞築壓) = 網鏇憲淵蓋醖鏇餘築願膚鑰築蓋鏇壓衊繭觸繭 (衊選簾廠廠齋膚齋鬱糧 )	-	2010-04-15