Delving into the Latest Updates on MK-0752 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

L-000891675, MK 0752

Target

γ-secretase

Action

inhibitors

Mechanism

γ-secretase inhibitors(Gamma-secretase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [3]

Active Indication-

Inactive Indication

Advanced breast cancerAdvanced cancerAlzheimer Disease+ [8]

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.Merck GmbHMerck Sharp & Dohme LLC

+ [2]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

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

NCT01098344

/ CompletedPhase 1IIT

A Cancer Research UK Phase I Trial of an Oral Notch Inhibitor (MK-0752) in Combination With Gemcitabine in Patients With Stage III and IV Pancreatic Cancer

RATIONALE: MK0752 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving MK0752 together with gemcitabine hydrochloride may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of giving MK0752 together with gemcitabine hydrochloride and to see how well it works in treating patients with stage III or IV pancreatic cancer that cannot be removed by surgery.

Start Date01 Apr 2010

Sponsor / Collaborator

Cancer Research UK

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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66

Literatures (Medical) associated with MK-0752

01 Apr 2025·NATURE STRUCTURAL & MOLECULAR BIOLOGY

Structural basis of human γ-secretase inhibition by anticancer clinical compounds

Article

Author: Lu, Xiaoli ; Zhou, Rui ; Shi, Yigong ; Lei, Jianlin ; Liu, Hao ; Yan, Chuangye ; U, Kaicheng ; Huang, Jing ; Li, Haotian ; Guo, Xuefei

Aberrant activation of Notch signaling, mediated by the Notch intracellular domain (NICD), is linked to certain types of cancer. The NICD is released through γ-secretase-mediated cleavage of the Notch receptor. Therefore, development of a γ-secretase inhibitor (GSI) represents an anticancer strategy. Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. Three of the five GSIs are in active anticancer clinical trials, while nirogacestat was recently approved. Each of these GSIs similarly occupies the substrate-binding site of presenilin 1 but shows characteristic differences in detailed recognition pattern. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.

01 Dec 2024·MOLECULAR BIOLOGY REPORTS

17β-estradiol inhibits Notch1 activation in murine macrophage cell line RAW 264.7

Article

Author: Vieceli Dalla Sega, Francesco ; Fortini, Francesca ; Marracino, Luisa ; Ouambo Talla, Achille Wilfred ; Minghini, Giada ; Scarpante, Irene ; Haffreingue, Louis ; Dalessandro, Francesca ; Martino, Valeria ; Ascierto, Alessia ; Severi, Paolo ; Aquila, Giorgio ; Rizzo, Paola

BACKGROUND:

Macrophages are major effectors in regulating immune response and inflammation. The pro-inflammatory phenotype (M1) is induced by the activation of the Toll-like receptor 4 (TLR4) on the macrophage surface, which recognizes lipopolysaccharide (LPS), a component of Gram-negative bacterial wall, and by the binding of interferon-gamma (IFNγ), a cytokine released by activated T lymphocytes, to its receptor (IFNGR). Among the pathways activated by LPS/IFNγ is the Notch pathway, which promotes the M1 phenotype. Conversely, 17β-estradiol (E2) has been shown to blunt LPS-mediated inflammatory response. While it has been shown that E2 regulates the activity of the Notch1 receptor in human endothelial cells, there is no evidence of estrogen-mediated regulation of Notch1 in macrophages.

METHODS AND RESULTS:

In this study, RAW 264.7 cells were stimulated with LPS/IFNγ in the presence or absence of E2 and/or N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, the enzyme involved in Notch activation. The effects of treatment on inducible nitric oxide synthase (iNOS), on components of the Notch pathway, and MAPK (mitogen-activated protein kinase) were assessed by quantitative PCR and Western blotting. We found that E2, through a mechanism involving the inhibition of p38 phosphorylation, reduces the activation of Notch1 induced by LPS/IFNγ. On the contrary, Notch1 exerts a negative control on the estrogen receptor α (ERα) since Notch1 inhibition increases the protein levels of this receptor.

CONCLUSION:

In conclusion, we report for the first time a Notch-ERα interaction in macrophages. Our data suggest that E2 may reduce LPS/IFNγ-mediated M1 pro-inflammatory phenotype in macrophages by inhibiting Notch1. This finding encourages further studies on Notch1 inhibitors as novel treatments for inflammation-related diseases.

01 Dec 2023·Endocrine, metabolic & immune disorders drug targets

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

Article

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

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).

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	United States	Merck Sharp & Dohme Corp.	01 Mar 2008
Locally advanced breast cancer	Phase 2	United States	Merck Sharp & Dohme Corp.	01 Mar 2008
Metastatic breast cancer	Phase 2	United States	Merck Sharp & Dohme Corp.	01 Mar 2008
Breast Cancer	Phase 2	-	National Cancer Institute	-
Pancreatic Cancer	Phase 2	-	Merck Sharp & Dohme Corp.	-
Pancreatic Cancer	Phase 2	-	National Cancer Institute	-
Advanced cancer	Phase 1	-	Merck Sharp & Dohme LLC	22 Nov 2010
Pancreatic carcinoma non-resectable	Phase 1	United Kingdom	Cancer Research UK	01 Apr 2010
Alzheimer Disease	Phase 1	-	Merck Sharp & Dohme Corp.	01 Dec 2008
Central Nervous System Neoplasms	Phase 1	United States	National Cancer Institute	01 Jul 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01098344 (Pubmed \| Med J Aust) Manual	Phase 1	Pancreatic Ductal Adenocarcinoma	44	gemcitabine+MK-0752	cxygbqrebq(ivspjlwcyd) = MK-0752 1800 mg, gemcitabine 1000 mg m-2 lqecmddtzm (bhszxcystz ) View more	Positive	20 Mar 2018
NCT01243762 (0646-027, CTgov)	Phase 1	Advanced cancer	47	MK-0752+dalotuzumab (Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg)	mdzkggffuv = rjtpcngwca nscuqnaotc (jclpbwconv, npdfvdydfr - euheqgkgoo) 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)	mdzkggffuv = yyshsscwzq nscuqnaotc (jclpbwconv, zeuzjyouxb - epvuguoxlk) View more	-	30 Oct 2017
NCT01295632 (8669-049, Pubmed \| Eur J Cancer Care (Engl) \| Eur J Cancer) Manual	Phase 1	Advanced Malignant Solid Neoplasm	28	ridaforolimus+MK-0752	dbnnplemua(vxblwqkijf) = fdzrfnlpao tpnmaetssg (rlugjxxmfp ) View more	Positive	01 Sep 2015
NCT00572182 (Pubmed \| Childs Nerv Syst) Manual	Phase 1	Neoplasms	10	MK-0752	xtvggbcigx(rokzzrlrsn) = 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. udtjqqannk (mvkvjrmcun )	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)	hwjfxhfdej = oqsdcylkut exaoskjohc (swfuydpojc, btngttfqeb - qbefrztkln) View more	-	04 Apr 2014
NCT00645333 (CTgov)	Phase 1/2		30	pegfilgrastim+MK-0752+docetaxel (MK-0752)	czbytwiioc(rjdjainiel) = wqbipwszno rizngbhznn (ceefrvhvjk, halyzvyjyd - koquygiocu) View more	-	04 Apr 2014
ASCO2006	Phase 1	T-cell Acute Lymphoblastic Leukemia/Lymphoma \| Leukemia	8	MK-0752	kchnhdhefh(gbloumgmnm) = eehhkxonyo fjchxcfqso (fjzlnvwqax ) View more	-	20 Jun 2006