Delving into the Latest Updates on LCL-161 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

IAP

Mechanism

Inhibitors of apoptosis (IAP) protein family inhibitors

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesEndocrinology and Metabolic Disease+ [7]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmColorectal CancerNon-Small Cell Lung Cancer+ [6]

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.US Oncology Research LLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC26H33FN4O3S

InChIKeyUFPFGVNKHCLJJO-SSKFGXFMSA-N

CAS Registry1005342-46-0

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.

Start Date23 Mar 2016

Sponsor / Collaborator

SCRI Development Innovations, LLC

[+1]

100 Clinical Results associated with LCL-161

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100 Translational Medicine associated with LCL-161

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100 Patents (Medical) associated with LCL-161

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96

Literatures (Medical) associated with LCL-161

01 Sep 2024·Heliyon

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

Article

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

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

01 Aug 2024·Mini-Reviews in Medicinal Chemistry

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects

Review

Author: Wal, Pranay ; Bisht, Priya ; Kumar, Nitesh ; Murti, Krishna ; Pandey, Ruchi ; Ravichandiran, V

Background:Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades.Objective:This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer.Method:Articles were analysed using search engines and databases namely Pubmed and Scopus.Result:Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation.Conclusion:SMAC mimetics acts in a restorative way in the prevention of lung cancer.

01 Jul 2024·Acta Pharmaceutica Sinica B

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

Article

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

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.

100 Deals associated with LCL-161

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12085

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Triple Negative Breast Cancer	Phase 2	CZ	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	RU	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	BR	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	GB	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	US	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	TW	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	AU	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	KR	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	IE	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	IT	Novartis Pharmaceuticals Corp.	01 Aug 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02649673 (Pubmed)	Phase 1	Small cell lung cancer recurrent \| Female Genital Neoplasms	35	LCL161 plus Oral Topotecan	(hjvywsfjmw) = kfawkkkbto qcztwlhyvh (mmjjclwhge ) View more	Negative	02 May 2023
NCT01617668 (Pubmed) Manual	Phase 2	Triple Negative Breast Cancer ER Negative \| PR Negative \| HER2 Negative	209	Paclitaxel+LCL 161	(bwfmmamdpl) = gfukjtvwlf nogyoaeaqm (ojabbekptb ) View more	Positive	20 Sep 2018
NCT01617668 (Pubmed) Manual	Phase 2		209	Paclitaxel	(bwfmmamdpl) = jzfqeldjsx nogyoaeaqm (ojabbekptb ) View more	Positive	20 Sep 2018
NCT01617668 (ASCO2015)	Phase 2	Triple Negative Breast Cancer Neoadjuvant	209	LCL161 with paclitaxelLCL161 with paclitaxel	(sygtsgtswp) = gopgjlkvtq avijhnvghp (vfogvafijs )	-	20 May 2015
NCT01617668 (ASCO2015)	Phase 2	Triple Negative Breast Cancer Neoadjuvant	209	Paclitaxel alone	(sygtsgtswp) = dlonpymnzn avijhnvghp (vfogvafijs )	-	20 May 2015
AACR2010	Phase 1	Advanced cancer	27	LCL161	ufmklxdepy(xibtnyvyos) = umfitikfay whztysvgso (kjulptkuyd )	-	15 Apr 2010