Delving into the Latest Updates on MK-8353 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

MK 8353, SCH-900353

Target

ERK1 x ERK2

Mechanism

ERK1 inhibitors(Extracellular-signal-regulated kinase1 inhibitors), ERK2 inhibitors(Extracellular-signal-regulated kinase 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Colorectal Cancer

Inactive Indication

Advanced Malignant Solid NeoplasmFGF19 positive Solid Tumors

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization

Merck Sharp & Dohme Corp.

Inactive Organization

Merck Sharp & Dohme LLC

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC37H42ClN9O3S

InChIKeyMAEYDGFPLZDKHE-JFRIYMKVSA-N

CAS Registry1951448-73-9

This is a multicenter, worldwide, open-label study of MK-8353 in combination with selumetinib in participants with histologically or cytologically confirmed diagnosis of advanced solid tumor. This study will evaluate the safety, tolerability, and exploratory efficacy of MK-8353 in combination with selumetinib.

Start Date22 Feb 2019

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT02972034 / CompletedPhase 1

A Phase Ib Study to Evaluate the Safety and Tolerability of MK-8353 in Combination With Pembrolizumab in Patients With Advanced Malignancies

This study will evaluate the safety, tolerability and preliminary efficacy of MK-8353 when administered in combination with pembrolizumab (MK-3475). There are two parts in this study: Part 1 will be dose escalation and confirmation, and Part 2 will be a cohort expansion. In Part 1, the recommended phase II dose (RP2D) of MK-8353 in combination with a fixed dose of pembrolizumab in participants with advanced malignancies will be identified and confirmed. Participants will be initially enrolled to receive MK-8353 at 350 mg twice a day (BID) in combination with pembrolizumab at a fixed dose of 200 mg on Day 1 of each 3-week cycle (Q3W) for up to 24 months of treatment. In Part 2, participants with advanced colorectal cancer (CRC) that is microsatellite stable (i.e., non-microsatellite instability-high/deficient mismatch repair [non-MSI-H/dMMR]) who received at least one and up to five prior lines of therapy will be enrolled at the RP2D in the expansion cohort to further evaluate safety and efficacy.
The protocol has been amended to lower the starting doses of MK-8353 in combination with pembrolizumab. In addition, 3 arms have been added: one in which MK-8353 will be administered continuously once a day (QD) in combination with pembrolizumab, one optional arm in which MK-8353 will be administered 1 week on/1 week off QD in combination with pembrolizumab and one optional arm in which participants undergo a MK-8353 QD run-in period prior to starting combination therapy with pembrolizumab.

Start Date13 Jan 2017

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NL-OMON37039 / SuspendedNot Applicable

A Phase 1 Study to Evaluate the Safety, Tolerability and Efficacy of MK-8353 Combination Therapies in Subjects With Advanced Solid Tumors - MK8353-010

Start Date03 Dec 2012

Sponsor / Collaborator-

100 Clinical Results associated with MK-8353

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100 Translational Medicine associated with MK-8353

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100 Patents (Medical) associated with MK-8353

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7

Literatures (Medical) associated with MK-8353

01 Jun 2023·Investigational new drugs

Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.

Article

Author: Renouf, Daniel J. ; Nayak, Tapan ; Freshwater, Tomoko ; Suttner, Leah H. ; Webber, Andrea L. ; Stathis, Anastasios ; Wang, Judy S. ; Tolcher, Anthony W. ; Chen, Lin-Chi ; Siu, Lillian L.

AIM:

We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors.

METHODS:

This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy.

RESULTS:

Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg).

CONCLUSION:

MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.

29 Mar 2023·Journal of experimental & clinical cancer research : CR

FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation.

Article

Author: Wang, Changxing ; Shen, Jingyi ; Lu, Chenchen ; Liu, Jing ; Guo, Yuqing ; Wu, Meiying ; Ma, Sai ; Liang, Zhipan ; Gao, Yingyin ; Li, Yinyan ; Pan, Yunzhi ; Qian, Yulan

BACKGROUND:

Increasing evidence suggests that FBXW7 has a high frequency of mutations in esophageal squamous cell carcinoma (ESCC). However, the function of FBXW7, especially the mutations, is not clear. This study was designed to investigate the functional significance of FBXW7 loss of function and underlying mechanism in ESCC.

METHODS:

Immunofluorescence was applied to clarify the localization and main isoform of FBXW7 in ESCC cells. Sanger sequencing were performed to explore mutations of FBXW7 in ESCC tissues. Proliferation, colony, invasion and migration assays were performed to examine the functional roles of FBXW7 in ESCC cells in vitro and in vivo. Real-time RT-PCR, immunoblotting, GST-pulldown, LC-MS/MS and co-immunoprecipitation assay were used to explore the molecular mechanism underlying the actions of FBXW7 functional inactivation in ESCC cells. Immunohistochemical staining were used to explore the expression of FBXW7 and MAP4 in ESCC tissues.

RESULTS:

The main FBXW7 isoform in ESCC cells was the β transcript in the cytoplasm. Functional inactivation of FBXW7 led to activation of the MAPK signaling pathway and upregulation of the downstream MMP3 and VEGFA, which enhanced tumor proliferation cell invasion and migration. Among the five mutation forms screened, S327X (X means truncated mutation) had an effect similar to the FBXW7 deficiency and led to the inactivation of FBXW7 in ESCC cells. Three other point mutations, S382F, D400N and R425C, attenuated but did not eliminate FBXW7 function. The other truncating mutation, S598X, which was located outside of the WD40 domain, revealed a tiny attenuation of FBXW7 in ESCC cells. Notably, MAP4 was identified as a potential target of FBXW7. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. Immunohistochemical staining indicated that FBXW7 loss of function was associated with tumor stage and shorter survival of patients with ESCC. Univariate and multivariate Cox proportional hazards regression analyses showed that high FBXW7 and low MAP4 was an independent prognostic indicator and prospective longer survival. Moreover, a combination regimen that included MK-8353 to inhibit the phosphorylation of ERK and bevacizumab to inhibit VEGFA produced potent inhibitory effects on the growth of FBXW7 inactivation xenograft tumors in vivo.

CONCLUSIONS:

This study provided evidence that FBXW7 loss of function promoted ESCC via MAP4 overexpression and ERK phosphorylation, and this novel FBXW7/MAP4/ERK axis may be an efficient target for ESCC treatment.

01 Jul 2020·Pathology internationalQ4 · MEDICINE

S100A12 promotes inflammation and apoptosis in ischemia/reperfusion injury via ERK signaling in vitro study using PC12 cells

Q4 · MEDICINE

Article

Author: Chen, Zuoquan ; Shu, Zhongwen ; Zhang, Quanbin ; Zhang, Xiang ; Shen, Rui

S100A12 is a member of S100 calcium‐binding proteins with effect to promote inflammation in brain damage and stroke. However, the role of S100A12 in ischemia/reperfusion (I/R) remains to be clarified. This study aimed to explore the effect of S100A12 on I/R and discover the possible mechanism. Oxygen‐glucose deprivation and reperfusion (OGD/R) was used to induce I/R injury model in vitro. Knockdown or overexpression of S100A12 was utilized to explore the role of S100A12 in I/R‐induced inflammation and apoptosis. Results indicated that S100A12 expression was dramatically upregulated after OGD/R. Knockdown of S100A12 inhibited, while overexpression of S100A12 enhanced, the activation of ERK1/2 protein. OGD/R also triggered the occurrence of inflammation and oxidative stress, while these effects were blunted by S100A12 silencing and aggravated by S100A12 overexpression, and the presence of MAP kinase signaling system (ERK) inhibitor MK‐8353 counteracted the effect of S100A12 overexpression. Besides, S100A12 silencing abolished, while its overexpression restored, the OGD/R‐induced increased apoptosis rate and pro‐apoptotic proteins expression. Similarly, ERK inhibitor MK‐8353 reversed the effects of S100A12 overexpression. In conclusion, S100A12 promoted OGD/R‐induced inflammation, oxidative stress and apoptosis via activation of ERK signaling in vitro.

100 Deals associated with MK-8353

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
FGF19 positive Solid Tumors	Phase 1	US	Merck Sharp & Dohme Corp.	22 Feb 2019
FGF19 positive Solid Tumors	Phase 1	CA	Merck Sharp & Dohme Corp.	22 Feb 2019
FGF19 positive Solid Tumors	Phase 1	CH	Merck Sharp & Dohme Corp.	22 Feb 2019
Solid tumor	Phase 1	US	Merck Sharp & Dohme Corp.	22 Feb 2019
Solid tumor	Phase 1	CA	Merck Sharp & Dohme Corp.	22 Feb 2019
Solid tumor	Phase 1	CH	Merck Sharp & Dohme Corp.	22 Feb 2019
Colorectal Cancer	Phase 1	US	Merck Sharp & Dohme Corp.	13 Jan 2017
Colorectal Cancer	Phase 1	CA	Merck Sharp & Dohme Corp.	13 Jan 2017
Advanced Malignant Solid Neoplasm	Phase 1	-	Merck Sharp & Dohme LLC	04 Nov 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03745989 (MK-8353-014 \| 8353-014, CTgov)	Phase 1	Solid tumor	30	Selumetinib+MK-8353 (MK-8353 50 mg + Selumetinib 25 mg)	iisipsudsp(ecufjzokur) = assellwqqz judsnxrxto (kxrkirsdvr, fcklgrohgc - bplrrjdglu) View more	-	25 Jan 2023
				Selumetinib+MK-8353 (MK-8353 100 mg + Selumetinib 50 mg)	iisipsudsp(ecufjzokur) = jwsnaevucw judsnxrxto (kxrkirsdvr, fodgfaibtp - hvniliihla) View more
NCT01358331 (MK-8353-001 \| P06203, CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	25	MK-8353 (MK-8353 100 mg Twice Daily (BID))	ltkivjuuzo(ivekmialov) = ndnwnegpjb wbrtidrmtb (mtnkinnhne, ybqycirbjv - wnhypdyehw) View more	-	02 Apr 2020
				MK-8353 (MK-8353 200 mg BID)	ltkivjuuzo(ivekmialov) = hrvgjcoumd wbrtidrmtb (mtnkinnhne, hmgpzylntm - jfjunhenam) View more
NCT01358331 (MK-8353-001 \| P06203, Pubmed \| JCI Insight) Manual	Phase 1	HR-positive/HER2-low Solid Tumors BRAF V600 Mutation	26	MK-8353	qiveokjezm(ealwnssmrb) = xcudjhicvf ewjdptwwaq (nnzzalwmzb )	Positive	22 Feb 2018