Delving into the Latest Updates on R-4733 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [3]

Target

γ-secretase

Mechanism

γ-secretase inhibitors(Gamma-secretase inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesNervous System Diseases+ [12]

Active Indication-

Inactive Indication

Acidophil AdenomaAcoustic NeuromaAcute Lymphoblastic Leukemia+ [134]

Originator Organization

National Cancer Institute

Active Organization-

Inactive Organization

National Cancer InstituteHoffmann-La Roche, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H20F5N3O3

InChIKeyOJPLJFIFUQPSJR-INIZCTEOSA-N

CAS Registry847925-91-1

This phase II clinical trial is studying how well gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) after autologous stem cell transplant works in treating patients with multiple myeloma. Giving chemotherapy, such as melphalan, before autologous stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Before treatment, stem cells are collected from the patient's blood and stored. After chemotherapy, the stem cells are returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving RO4929097 after autologous stem cell transplant may kill more cancer cells.

Start Date01 Dec 2010

Sponsor / Collaborator

National Cancer Institute

NCT01238133 / TerminatedPhase 1IIT

A Phase 1 Study of Neoadjuvant Chemotherapy With the Gamma Secretase Inhibitor RO4929097 in Combination With Paclitaxel and Carboplatin in Patients With Clinical Stage II-III Triple Negative Breast Cancer

This phase I trial studies the side effects and the best dose of gamma-secretase inhibitor RO4929097 when given together with paclitaxel and carboplatin in patients with stage II or stage III triple-negative breast cancer. Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs use in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving gamma-secretase inhibitor RO4929097 together with paclitaxel and carboplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Start Date01 Dec 2010

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with R-4733

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100 Translational Medicine associated with R-4733

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100 Patents (Medical) associated with R-4733

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70

Literatures (Medical) associated with R-4733

01 Dec 2023·Molecular Diversity

Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach

Article

Author: Tripathi, Vishwas ; Camps, Ihosvany ; Mishra, Amaresh ; Pathak, Yamini

Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.

01 Jul 2023·Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway

Article

Author: Shi, Lei ; Zhang, Lidan

BACKGROUNDLung adenocarcinoma (LUAD) represents the predominant subtype of lung cancer. MELTF, an oncogene, exhibits high expression in various cancer tissues. Nevertheless, the precise role of MELTF in the progression of LUAD remains enigmatic. This work was devised to investigate the effect of MELTF on LUAD progression and its underlying mechanism.METHODSmRNA expression data of LUAD were from The Cancer Genome Atlas database, and the enrichment pathway of MELTF was analyzed. The upstream transcription factors of MELTF were predicted, and the correlation between MELTF and E2F1 as well as the expression of the two in LUAD tissues were dissected by bioinformatics. The expression of MELTF and E2F1 in LUAD tissues and cells was assayed by qRT-PCR. Effects of MELTF/E2F1 on proliferation, migration, and invasion of LUAD cells were tested by CCK-8, colony formation, and Transwell assays. The binding relationship between E2F1 and MELTF was estimated by dual-luciferase reporter gene assay and ChIP assay. Western blot was utilized to assay the expression of Notch signaling pathway-related proteins in different treatment groups.RESULTSBioinformatics analysis and qRT-PCR results exhibited high expression of E2F1 and MELTF in LUAD tissues and cells, respectively. Dual-luciferase reporter gene assay and ChIP assay ascertained the binding of E2F1 to MELTF. MELTF was ascertained to enrich the Notch signaling pathway by bioinformatics means. In cell experiments, MELTF was shown to foster the malignant progression of LUAD cells and promoted the expression of NOTCH1 and HES1 proteins, but RO4929097 offset the effect of MELTF on cells. Rescue assay confirmed that E2F1 activated MELTF to promote LUAD progression via the Notch signaling pathway.CONCLUSIONTogether, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.

13 Jun 2023·International journal of molecular sciences

Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment.

Article

Author: Chimento, Adele ; Andò, Sebastiano ; Malivindi, Rocco ; Conforti, Francesca Luisa ; Pezzi, Vincenzo ; Panno, Maria Luisa ; De Amicis, Francesca ; D'Amico, Maria ; Giordano, Francesca ; Montalto, Francesca Ida

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.

100 Deals associated with R-4733

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11870

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Kaposi Sarcoma	Phase 2	US	National Cancer Institute	01 Jun 2010
Mesenchymoma	Phase 2	US	National Cancer Institute	01 Jun 2010
progesterone receptor-negative breast cancer	Phase 2	CA	National Cancer Institute	01 Jun 2010
Synovial Sarcoma	Phase 2	US	National Cancer Institute	01 Jun 2010
Metastatic Colorectal Carcinoma	Phase 2	US	National Cancer Institute	01 May 2010
Recurrent Colon Cancer	Phase 2	US	National Cancer Institute	01 May 2010
Recurrent Colon Cancer	Phase 2	US	National Cancer Institute	01 May 2010
Non-squamous non-small cell lung cancer	Phase 2	NL	Hoffmann-La Roche, Inc.	01 Jan 2010
Recurrent Non-Small Cell Lung Cancer	Phase 2	NL	Hoffmann-La Roche, Inc.	01 Jan 2010
Recurrent Non-Small Cell Lung Cancer	Phase 2	NL	Hoffmann-La Roche, Inc.	01 Jan 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01149356 (Pubmed \| Clin Breast Cancer) Manual	Phase 1	Metastatic breast cancer	15	Exemestane+RO4929097	(gakutvbuoj) = hypophosphatemia (13%) and rash (6.3%) jcvuyocctl (imjmmonxoy ) View more	Positive	01 Feb 2022
NCT01122901 (Pubmed \| Neurosurgery) Manual	Phase 2	Glioblastoma	47	RO4929097	(qhqvnjkpck) = utujpcfdsn kwqtxcmzwb (oofxudfofk ) View more	Negative	13 Jan 2021
NCT01196416 (CTgov)	Phase 1/2	Melanoma, Cutaneous Malignant \| Melanoma recurrent \| Metastatic melanoma	14	Pharmacological Study+Gamma-Secretase Inhibitor RO4929097+Temozolomide+cisplatin+Vinblastine Sulfate	qrrubgsirc(tpqamepafx) = ddyltgbjbg xrddeddygf (ssbnzodaqa, exmtusbzab - atwhtkyuye) View more	-	18 Oct 2017
NCT01175343 (CTgov)	Phase 2	Recurrent ovarian cancer \| Recurrent Primary Peritoneal Carcinoma \| Platinum-Resistant Primary Peritoneal Carcinoma \| Fallopian Tube Carcinoma \| Platinum-Resistant Ovarian Carcinoma	45	Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097	etsxcfuzne(ljhrwmvypj) = epbynmqwdo ffsbbjmwik (hyqnoscvpm, skxxukvtit - fdzieamnks) View more	-	24 May 2017
NCT01151449 (CTgov)	Phase 2	Recurrent Triple-Negative Breast Carcinoma \| progesterone receptor-negative breast cancer \| Breast cancer recurrent \| Male Breast Neoplasms \| HER2-negative breast cancer \| Metastatic breast cancer \| Estrogen receptor-negative breast cancer \| Breast Cancer 3	6	laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097	ssfgtttuul(qcidiymdig) = oexdurivxd ahaluwhtwi (cekosiheru, lkjyfaekon - uwcrokoutu) View more	-	11 Apr 2017
NCT01141569 (CTgov)	Phase 2	Advanced Renal Cell Carcinoma	12	Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097	hsoixbkeje(zcgkkdexuf) = zsxmrhsbfl kxzdopnvpq (nivkrjndpu, ipokksarvg - ltdlmraxaf) View more	-	10 Mar 2017
NCT01189240 (Pubmed \| J Neurooncol) Manual	Phase 1	Recurrent Malignant Glioma	13	bevacizumab+RO4929097	(qgfenadlap) = not identified sdgwepytyb (uwappfhbvp )	Positive	01 Dec 2016
NCT01120275 (SWOG S0933 \| SWOG 0933, CTgov)	Phase 2	Melanoma recurrent \| Lentigo maligna melanoma \| Malignant melanoma stage IV	36	laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097	aogmholzxp(mpqatknlpj) = cxczlpqyyh avgaxpbunn (bppokijayd, axklyukwxe - wdsevzpqpx) View more	-	14 Jun 2016
NCT01193868 (CTgov)	Phase 2	Non-small cell lung cancer stage IIIB \| Advanced Lung Non-Small Cell Carcinoma \| Recurrent Non-Small Cell Lung Cancer	6	pharmacological study+gamma-secretase/Notch signalling pathway inhibitor RO4929097	(dfylnbfwpg) = xmcwackfpp kxdqeaqxsp (rwojwngalt, zrgxrapjfq - kyztijhoie) View more	-	18 Nov 2015
NCT01189240 (CTgov)	Phase 1/2	Gliosarcoma \| Glioblastoma \| Oligodendroglioma \| Recurrent Malignant Glioma	13	pharmacological study+gamma-secretase/Notch signalling pathway inhibitor RO4929097+bevacizumab (Phase I Dose Finding)	zokzqeaksz(xuwewpbyhq) = docxbvhtim wrjzjjrvcp (ughpluhnix, nxqzxmqpvo - lfigsmtdcb) View more	-	14 Jul 2015
NCT01189240 (CTgov)	Phase 1/2		13	pharmacological study+gamma-secretase/Notch signalling pathway inhibitor RO4929097+bevacizumab (Phase I Dose Finding - Level 1 5mg)	gjqokcrrjx(uyxfgsdflh) = omtihpjlqp rhptmgpswn (qgmzzhbcby, ruxzbygiep - kvcyrdsour) View more	-	14 Jul 2015