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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98

项与 LCL-161 相关的文献（医药）

2025-01-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

cIAP2 supports the cell growth-promoting activity of FMR1 in gastric cancer via CARD-RING domains

Article

作者: Seo, Tae Woong ; Yoo, Soon Ji ; Kang, Ji Woo ; Lee, Yui Taek ; Heo, Jeong In

Fragile X Mental Retardation Protein 1 (FMR1) is a translational repressor crucial for regulating genes in the central nervous system. While a lack of FMR1 expression causes Fragile X Syndrome (FXS), its overexpression is implicated in various cancers, necessitating tight regulation of FMR1 protein levels for normal cell physiology. In this study, we report that FMR1 is upregulated in gastric cancer patients. Reducing FMR1 expression decreased cell growth in gastric cancer cell lines. The Smac Mimetic LCL161 reduced both FMR1 and cellular inhibitor of apoptosis protein 2 (cIAP2) levels. Suppressing cIAP2, but not cIAP1, led to decreased FMR1, while cIAP2 overexpression increased FMR1 in gastric cancer cells. We observed that cIAP2 is also upregulated in gastric cancer patients, with FMR1 and cIAP2 levels positively correlated in both gastric and colorectal cancers. Notably, cIAP2 binds FMR1 via its CARD domain, unlike most cIAP2 targets that bind the BIR domain. Furthermore, cIAP2 ubiquitinates FMR1 through its CARD-RING domains, stabilizing the protein without proteasomal degradation. FMR1, modulated by cIAP2, promotes gastric cancer cell growth. Collectively, our findings highlight FMR1's growth-promoting role in gastric cancer and reveal a novel function of cIAP2 in stabilizing FMR1 as an E3 ligase. These results suggest targeting cIAP2 could be an effective strategy for treating gastric cancer by downregulating both cIAP2 and FMR1.

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 ; Liu, Zhiwei ; Han, Yetao ; 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.

2024-07-01·Acta Pharmaceutica Sinica B

Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membrane-decorated nanoparticles

Article

作者: Wang, Hao ; Gong, Xiang ; Jiang, Yunxuan ; Zheng, Chao ; Zhai, Yihui ; Zhu, Helen He ; Zhang, Pengcheng ; Rong, Rong ; Zhu, Binyu ; Li, Yaping ; Cai, Ying ; Zhang, Wen

Current cytotoxic T lymphocyte (CTL) activating immunotherapy requires a major histocompatibility complex I (MHC-I)-mediated presentation of tumor-associated antigens, which malfunctions in around half of patients with triple-negative breast cancer (TNBC). Here, we create a LCL161-loaded macrophage membrane decorated nanoparticle (LMN) for immunotherapy of MHC-I-deficient TNBC. SIRPα on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161, which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells. The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds. LMNs also block CD47-mediated phagocytosis suppression. LMNs inhibit the growth of MHC-I-deficient TNBC tumors, as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel, and prolong the survival of animals, during which process CTLs also play important roles. This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.

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


NCT02649673 (Pubmed \| Oncologist)	临床1期	女性生殖器官肿瘤 \| 小细胞肺癌	35	LCL161 plus Oral Topotecan	鑰築夢廠糧壓膚糧範齋(獵膚艱餘構築網廠壓遞) = 襯構艱膚窪窪醖構襯鬱鬱鏇製構遞鬱夢餘醖糧 (網鹽選鬱膚餘網鏇窪構 ) 更多	不佳	2023-05-02
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	遞淵窪鏇廠廠憲遞願蓋(壓遞簾膚積鏇鑰衊積繭) = 願蓋積鬱醖積窪餘艱壓鹽顧膚獵窪艱觸壓網鏇 (鹹鹹鹹憲構鏇觸鑰蓋構 ) 更多	积极	2018-09-20
NCT01617668 (Pubmed) 人工标引	临床2期	三阴性乳腺癌 ER Negative \| PR Negative \| HER2 Negative	209	Paclitaxel	遞淵窪鏇廠廠憲遞願蓋(壓遞簾膚積鏇鑰衊積繭) = 製鹽鹹範簾積夢遞鏇鬱鹽顧膚獵窪艱觸壓網鏇 (鹹鹹鹹憲構鏇觸鑰蓋構 ) 更多	积极	2018-09-20
NCT01617668 (ASCO2015)	临床2期	三阴性乳腺癌新辅助	209	LCL161 with paclitaxel	獵蓋齋憲衊膚網醖壓蓋(壓齋鬱鑰鏇範鬱廠餘壓) = 夢餘蓋夢廠構鏇顧鏇壓壓遞鬱簾觸夢窪鏇壓築 (襯餘繭觸憲築憲網觸顧 )	-	2015-05-20
NCT01617668 (ASCO2015)	临床2期	三阴性乳腺癌新辅助	209	Paclitaxel alone	獵蓋齋憲衊膚網醖壓蓋(壓齋鬱鑰鏇範鬱廠餘壓) = 膚積簾窪鹹窪鹹鏇膚糧壓遞鬱簾觸夢窪鏇壓築 (襯餘繭觸憲築憲網觸顧 )	-	2015-05-20
AACR2010	临床1期	晚期癌症	27	LCL161	願簾廠構餘廠廠選廠糧(構觸衊蓋餘範製窪淵簾) = 鹹蓋衊顧簾餘憲網淵願簾繭淵鹹獵淵糧選醖夢 (壓選淵鏇顧醖淵夢壓窪 )	-	2010-04-15