Delving into the Latest Updates on LCL-161 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LCL 161, NVP-LCL161

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-

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

Login to view more data

100 Translational Medicine associated with LCL-161

Login to view more data

100 Patents (Medical) associated with LCL-161

Login to view more data

90

Literatures (Medical) associated with LCL-161

05 Jul 2106·Oncotarget

Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib

Article

Author: Heinrich, Michael ; Bauer, Sebastian ; Corless, Christopher ; Marino-Enriquez, Adrian ; Reis, Anna-Carina ; Mühlenberg, Thomas ; Podleska, Lars Erik ; Grunewald, Susanne ; Fletcher, Jonathan Alfred ; Treckmann, Jürgen ; Falkenhorst, Johanna ; Schuler, Martin

Gastrointestinal stromal tumors (GIST) exhibit a strong oncogenic dependency on KIT and KIT inhibitors confer long lasting disease stabilization in the majority of patients. Nonetheless, KIT inhibition alone does not cure GIST as a subset of GIST cells evade apoptosis and eventually develop resistance. Inhibitors of Apoptosis Proteins (IAPs) may confer resistance to drug-induced apoptosis. We observed that the mRNA and protein of IAPs XIAP (BIRC4) and survivin (BIRC5) were highly expressed in primary GIST tumors and cell line models. Amplification of the respective gene loci (BIRC2, BIRC3, BIRC4, BIRC5) was detected in 47% of GIST studied by SNP arrays. Whole exome analyses revealed a mutation of SMAC(DIABLO) in a heavily pretreated patient. Both, survivin (rank 62-92/11.194 tested proteins) and XIAP (rank 106-557/11.194) were found to be essential proteins for survival in a synthetic lethality screen. Expression of XIAP and survivin decreased upon KIT inhibition and may play a role in KIT-regulated pro-survival signaling. SMAC-mimetic treatment with LCL161 and TL32711 reduced cIAP1 and XIAP expression. Survivin inhibitor YM155 lead to transcriptional repression of BIRC5/survivin (YM155) and induced apoptosis. Combinational treatment with KIT inhibitors (imatinib, regorafenib) enhanced the proapoptotic effect. These findings support the combination of KIT inhibition with IAP antagonists in GIST.

01 Aug 2024·Mini reviews in medicinal chemistry

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

Review

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

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 Jan 2024·Journal of pharmacological sciences

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma

Article

Author: Arihara, Yohei ; Kikuchi, Shohei ; Nakamura, Hajime ; Takada, Kohichi ; Kamihara, Yusuke ; Sugama, Yusuke ; Sato, Tsutomu ; Wada, Akinori

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C₅₈H₇₈N₈O₈), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

100 Deals associated with LCL-161

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12085

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Triple Negative Breast Cancer	Phase 2	US	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	BR	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	CZ	Novartis Pharmaceuticals Corp.	01 Aug 2012
Triple Negative Breast Cancer	Phase 2	DE	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
Triple Negative Breast Cancer	Phase 2	RU	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	ES	Novartis Pharmaceuticals Corp.	01 Aug 2012

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

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	nnyvllocih(krikgnicid) = hsdoyjmdld ghnyhncgxm (vidkwuspmh ) 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	irvzhmiggx(gtasxkirou) = uptkddqfgx hqmhgrelic (ekkdvlpmtd ) View more	Positive	20 Sep 2018
NCT01617668 (Pubmed) Manual	Phase 2		209	Paclitaxel	irvzhmiggx(gtasxkirou) = hbhutomfhw hqmhgrelic (ekkdvlpmtd ) View more	Positive	20 Sep 2018
NCT01617668 (ASCO2015)	Phase 2	Triple Negative Breast Cancer Neoadjuvant	209	LCL161 with paclitaxelLCL161 with paclitaxel	ojedaydfsx(nmjsvgpvdt) = theqtxwwya xqaphcblpp (lsjrmvanqe )	-	20 May 2015
NCT01617668 (ASCO2015)	Phase 2	Triple Negative Breast Cancer Neoadjuvant	209	Paclitaxel alone	ojedaydfsx(nmjsvgpvdt) = oiiczlzczo xqaphcblpp (lsjrmvanqe )	-	20 May 2015
AACR2010	Phase 1	Advanced cancer	27	LCL161	gqiwnnqquh(tqrpfxgeeq) = tbmjlqxvup ldtlvbruuq (zcaadlccin )	-	15 Apr 2010