Delving into the Latest Updates on MK-0752 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

γ-secretase

Mechanism

γ-secretase inhibitors(Gamma-secretase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [5]

Active Indication-

Inactive Indication

Advanced breast cancerAdvanced cancerAlzheimer Disease+ [10]

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Cancer Research UK

Merck Sharp & Dohme Corp.Merck GmbH

+ [2]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC21H21ClF2O4S

InChIKeyXCGJIFAKUZNNOR-QCKZDCLWSA-N

CAS Registry471905-41-6

This is a two part study of the drug MK-8669 (ridaforolimus) given with MK-2206 or MK-0752. In Part A of the study, the preliminary maximum tolerated dose (MTD) of the drug combinations will be found by giving sequentially higher doses of the study drugs. An expansion cohort of participants may be enrolled to confirm the MTD. New cohorts at other dose levels may be enrolled, depending on the rate of dose limiting toxicities (DLTs) in the planned cohorts. In Part B, an assessment of the efficacy of the drug combinations against selected advanced cancers will be made so that a recommended dose to be used in Phase 2 studies (RPTD) can be found. As of 19 July 2012 the MK-0752 arms of the study were fully enrolled and closed to further recruitment. As of 30 November 2012, no additional participants with prostate cancer will be enrolled.

Start Date01 Feb 2011

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT01243762 / TerminatedPhase 1

Phase I Parallel Arm Study of MK-0646 (Dalotuzumab) + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 (Ridaforolimus) Doublets (MK-MK Doublets) in Patients With Advanced Cancer

This is an open-label, two-part study to evaluate the safety and tolerability of combination treatment with dalotuzumab + MK-2206, dalotuzumab + MK-0752, or dalotuzumab + ridaforolimus (MK-8669). Part 1 of the study will determine the dose-limiting toxicities (DLTs) observed after administration of each of the combinations at various doses and define the maximum tolerated dose (MTD) of each combination. Part 2 of the study will assess preliminary anti-tumor activity of these combinations (at MTD) in two groups of participants with selected tumor biomarkers: one group with metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and one group with metastatic or recurrent colorectal cancer. The dalotuzumab + ridaforolimus and dalotuzumab + MK-2206 arms will be enriched with female platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer participants. The dalotuzumab + MK-0752 arm will be enriched with metastatic or recurrent wild-type kirsten rat sarcoma (KRAS) colorectal cancer participants.
The primary hypothesis is that the DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of each of the MK-MK doublets will be dose-dependent to allow for definition of a MTD within each MK-MK doublet.

Start Date22 Nov 2010

Sponsor / Collaborator

Merck Sharp & Dohme LLC

NCT00803894 / CompletedPhase 1

A Randomized Clinical Trial to Study the Effects of MK0752 Versus Placebo on Biomarkers in Healthy Young Adult Male Subjects

The purpose of this study is to determine the transcriptional signature of Notch Inhibition by testing hair and blood samples on healthy male volunteers who have received MK0752 vs placebo for possible future biomarkers in the treatment of cancer or Alzheimers Disease

Start Date01 Dec 2008

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-0752

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100 Translational Medicine associated with MK-0752

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100 Patents (Medical) associated with MK-0752

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25

Literatures (Medical) associated with MK-0752

01 Dec 2023·Endocrine, Metabolic & Immune Disorders - Drug Targets

Effect of Notch Signal Pathway on Steroid Synthesis Enzymes in TM3 Cells

Article

Author: Zheng, Yuxiang ; Li, Xiao ; Han, Suo ; Wang, Wei ; Zhang, Hongdan ; Wu, Zaichao ; Wang, Jing ; Zhang, Chunping

Background:Studies have indicated that the conservative Notch pathway contributes to steroid hormone synthesis in the ovaries; however, its role in hormone synthesis of the testis remains unclear. We have previously reported Notch 1, 2, and 3 to be expressed in murine Leydig cells and that inhibition of Notch signaling caused G0/G1 arrest in TM3 Leydig cells.Methods:In this study, we have further explored the effect of different Notch signal pathways on key steroidogenic enzymes in murine Leydig cells. TM3 cells were treated with Notch signaling pathway inhibitor MK-0752, and different Notch receptors were also overexpressed in TM3 cells.Results:We evaluated the expression of key enzymes of steroid synthesis, including p450 choles-terol side-chain cleavage enzyme (P450Scc), 3β-hydroxysteroid dehydrogenase (3β-HSD) and steroidogenic acute regulatory protein (StAR), and key transcriptional factors for steroid synthesis, including steroidogenic factor 1 (SF1), GATA-binding protein 4 (GATA4) and GATA6.Conclusion:We found the level of P450Scc, 3β-HSD, StAR and SF1 to be decreased after treat-ment with MK-0752, while overexpression of Notch1 up-regulated the expression of 3β-HSD, P450Scc, StAR and SF1. MK-0752 and overexpression of different Notch members had no influ-ence on the expression of GATA4 and GATA6. In conclusion, Notch1 signaling may contribute to the steroid synthesis in Leydig cells through regulating SF1 and downstream steroidogenic en-zymes (3β-HSD, StAR and P450Scc).

01 Nov 2023·Journal of cancer research and clinical oncology

In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma.

Article

Author: Haas, Markus ; Lein, Alexander ; Brkic, Faris F ; Kadletz-Wanke, Lorenz ; Varatanovic, Sara ; Stoiber, Stefan

PURPOSEGamma-secretase inhibitor MK0752 has shown a high therapeutic potential in different solid malignant tumors. Up to now, its antineoplastic effects were not investigated in head and neck squamous cell carcinoma (HNSCC) and particularly in human-papillomavirus (HPV)-positive tumors.METHODSWe conducted cytotoxic, migration, and clonogenic assays in two HPV-negative HNSCC cell lines (Cal27 and FaDu) and one HPV-positive cell line (SCC154). Furthermore, in order to assess the pro-apoptotic effects of MK0752, a Caspase 3/7 Glo assay was performed.RESULTSOur experiments revealed antineoplastic effects of MK0752 in all three cell lines. Strong cytotoxic and antimigratory potential was shown in all cell lines, with strongest effects observed in the HPV-positive cell line. Meanwhile, anticlonogenic effects were only shown in Cal27 and SCC154. Most importantly, MK0752 induced apoptosis solely in HPV-positive SCC154.CONCLUSIONSOur novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.

01 Jan 2023·Wiadomości Lekarskie

NEPHROPROTECTIVE EFFECT OF GAMMA-SECRETASE INHIBITOR ON SEPSIS- INDUCED RENAL INJURY IN MOUSE MODEL OF CLP

Article

Author: Hadi, Najah R ; Mardan, Haider W ; Majeed, Sahar A ; Ghafil, Fadha Abdulameer ; Qassam, Heider

The aim: This study was set out to assess the potential protective impact of MK0752 (a gamma secretase inhibitor) on sepsis-induced renal injury through modulation of inflammatory and oxidative stress pathways. Materials and methods: Twenty-four Swiss-albino mice aged between eight and twelve week and weighted twenty to thirty-seven grams were randomly allocated into four groups (n=6 in each group). Sham group (laparotomy without cecal ligation and puncture (CLP), sepsis group (laparotomy with CLP), vehicle-treated group (equivalent volume of DMSO before the CLP), MK0752 treated group (5 mg/kg) single daily dose for three days before the CLP. Blood samples were used to assess the serum levels of urea and creatinine. The kidneys were used to assess tissue levels of the TNF-α, IL-10, IL-6, TNFR1, VEGF, notch1, jagged1 and tissue damage by histopathological analysis. Results: The current study shows that pretreatment with MK0752 ameliorates the renal damage by significantly reducing the proinflammatory cytokines and notch1 signaling. Conclusions: Taken together, these results suggest that MK0752 could be protective against the renal injury induced by sepsis through its ameliorative impact on renal architecture and modulating cytokines and Notch1 singling pathway. Further studies regarding the role of Notch signaling pathways would be worthwhile.

100 Deals associated with MK-0752

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12852

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced breast cancer	Phase 2	US	Merck Sharp & Dohme Corp.	01 Mar 2008
Metastatic breast cancer	Phase 2	US	Merck Sharp & Dohme Corp.	01 Mar 2008
Breast Cancer	Phase 2	-	Merck Sharp & Dohme Corp.	-
Breast Cancer	Phase 2	-	National Cancer Institute	-
Central Nervous System Neoplasms	Phase 2	US	Merck GmbH	-
Central Nervous System Neoplasms	Phase 2	US	Merck GmbH	-
Hematologic Neoplasms	Phase 2	US	Merck GmbH	-
Pancreatic Cancer	Phase 2	-	Merck Sharp & Dohme Corp.	-
Pancreatic Cancer	Phase 2	-	National Cancer Institute	-
Locally advanced breast cancer	Phase 1	US	Merck Sharp & Dohme Corp.	01 Mar 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01243762 (0646-027, CTgov)	Phase 1	Advanced cancer	47	MK-0752+dalotuzumab (Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg)	ffppczxuhg(pxudnboreq) = vzozcfprpa usvskgikea (llfloqhoul, ewchjzvkrx - rljhwuogbk) View more	-	30 Oct 2017
NCT01243762 (0646-027, CTgov)	Phase 1	Advanced cancer	47	MK-0752+dalotuzumab (Dalotuzumab 10 mg/kg + MK-0752 1800 mg)	ffppczxuhg(pxudnboreq) = owkgdpuajs usvskgikea (llfloqhoul, lrsabnuxsi - wvyqoblhac) View more	-	30 Oct 2017
NCT01295632 (8669-049, Pubmed \| Eur J Cancer Care (Engl)) Manual	Phase 1	Advanced Malignant Solid Neoplasm	28	ridaforolimus+MK-0752	(sogrifsvbh) = dvfgsxyyhi bconwjaadr (qecsoyhzqd ) View more	Positive	01 Sep 2015
NCT00572182 (Pubmed \| Childs Nerv Syst) Manual	Phase 1	Neoplasms	10	MK-0752	(uvltyrywda) = One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. asymypizny (jjyozuwxsu )	Positive	01 Aug 2015
NCT00645333 (CTgov)	Phase 1/2	Locally advanced breast cancer \| Metastatic breast cancer \| Advanced breast cancer	30	MK-0752+Docetaxel (MK-0752 and Docetaxel)	(zazocymhdt) = aisalwrqjs ftfbracbyu (nxkiwyubal, xudglkkzzo - pamxytyqyl) View more	-	04 Apr 2014
NCT00645333 (CTgov)	Phase 1/2		30	pegfilgrastim+MK-0752+docetaxel (MK-0752)	yyzucfljdw(bkfgvzxepc) = egncpmavkw eljcwzjfff (rkagcsbjgy, lcqqyygfyy - vjdoggewku) View more	-	04 Apr 2014
ASCO2006	Phase 1	T-cell Acute Lymphoblastic Leukemia/Lymphoma \| Leukemia	8	MK-0752	(yrvsdxeqhm) = yrpeciyijp bfctqfrvan (wpfhfufvbj ) View more	-	20 Jun 2006