Delving into the Latest Updates on Doramapimod with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Doramapimod (USAN/INN)

+ [6]

Target

p38 MAPK

Mechanism

p38 MAPK inhibitors(P38 mitogen-activated protein kinase inhibitors)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal DiseasesDigestive System Disorders+ [1]

Active Indication-

Inactive Indication

Crohn DiseaseEndotoxin HyporesponsivenessNeoplasms+ [3]

Originator Organization

C.H. Boehringer Sohn AG & Co. KG

Active Organization

RespiVert Ltd.

Inactive Organization

C.H. Boehringer Sohn AG & Co. KG

Boehringer Ingelheim GmbH

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H37N5O3

InChIKeyMVCOAUNKQVWQHZ-UHFFFAOYSA-N

CAS Registry285983-48-4

Acute myeloid leukemia (AML), an uncommonly low 5-year survival and high mortality rate, is a potentially catastrophic diagnosed subtype of leukemia. The development of new prognostic markers is urgently needed to guide its treatment. Necroptosis is a newly defined biological process for regulating cell death, and previous studies have confirmed that the abnormality of the physical function can lead to multiple malignancies. Here, we performed necroptosis-related genes (NRGs) to build a predictive model in the Cancer Genome Atlas (TCGA)-AML patients, thus exploring the correlation between the NRG prognosis signature (NRG score) of this model and immune infiltration, pathway activity, clinical features, and immunotherapy. Besides, we computed the statistical measure Spearman rank correlation between the NRG score and the Log IC50 values of therapeutic agents. Subsequently, we divided the TCGA-AML cohort into 2 groups, one with high scores and the other with low scores depending on the model score. AML patients with high NRG scores exhibited a lower estimated overall survival (OS) rate than those with low NRG scores, which was confirmed in the validation set. The prognostic value of the constructed NRG signature to the AML, independent of other variables, was demonstrated by uni- and multivariate stepwise regression analysis. When comparing the infiltrating states of specialized cells associated with immune system from the 2 groups, B cells naive, Plasma cells, and monocytes represented significant differences among various subgroups of samples. Moreover, the 30 hallmark-related pathways related to necroptosis characteristics were remarkably different between the high/low NRG score groups. And patients showed remarkable NRG score distribution in clinical features of bone marrow lymphocyte, category, and FAB classifications. Besides, we found that the BIRB0796, VX680, Vorinostat, and Axitinib positively related with NRG score, whereas CI. 1040, PD. 0325901, Z.L LNle. CHO, and AZD6244 negatively correlated with the NRG score. These drugs may provide a reference for subsequent treatment.

15 Mar 2024·Journal of Clinical Investigation

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma

Article

Author: Hanly, Ailish ; Kalin, Jay H ; Gibson, Frederick ; Cole, Matthew ; Nocco, Sarah ; Alani, Rhoda M ; Park, Kihyun ; Labadorf, Adam ; Xiao, Amy ; Zuger, Angelina ; Collard, Marianne ; Cole, Philip A ; Wu, Muzhou ; Agus, Filisia ; Rogers, Samantha ; Kuang, Kevin ; Fisher, Robert ; Beck, Samuel

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

01 Jan 2024·Frontiers in immunology

Circulating IL-17F, but not IL-17A, is elevated in severe COVID-19 and leads to an ERK1/2 and p38 MAPK-dependent increase in ICAM-1 cell surface expression and neutrophil adhesion on endothelial cells.

Article

Author: Fraser, Douglas D ; Emad, Amin ; Bédard-Matteau, Jérôme ; Liu, Katelyn Yixiu ; Rousseau, Simon ; Soulé, Antoine ; Fourcade, Lyvia

BackgroundSevere COVID-19 is associated with neutrophilic inflammation and immunothrombosis. Several members of the IL-17 cytokine family have been associated with neutrophilic inflammation and activation of the endothelium. Therefore, we investigated whether these cytokines were associated with COVID-19.MethodsWe investigated the association between COVID-19 and circulating plasma levels of IL-17 cytokine family members in participants to the Biobanque québécoise de la COVID-19 (BQC19), a prospective observational cohort and an independent cohort from Western University (London, Ontario). We measured the in vitro impact of IL-17F on intercellular adhesion molecule 1 (ICAM-1) cell surface expression and neutrophil adhesion on endothelial cells in culture. The contribution of two Mitogen Activated Protein Kinase (MAPK) pathways was determined using small molecule inhibitors PD184352 (a MKK1/MKK2 inhibitor) and BIRB0796 (a p38 MAPK inhibitor).ResultsWe found increased IL-17D and IL-17F plasma levels when comparing SARS-CoV-2-positive vs negative hospitalized participants. Moreover, increased plasma levels of IL-17D, IL-17E and IL-17F were noted when comparing severe versus mild COVID-19. IL-17F, but not IL-17A, was significantly elevated in people with COVID-19 compared to healthy controls and with more severe disease. In vitro work on endothelial cells treated with IL-17F for 24h showed an increase cell surface expression of ICAM-1 accompanied by neutrophil adhesion. The introduction of two MAPK inhibitors significantly reduced the binding of neutrophils while also reducing ICAM-1 expression at the surface level of endothelial cells, but not its intracellular expression.DiscussionOverall, these results have identified an association between two cytokines of the IL-17 family (IL-17D and IL-17F) with COVID-19 and disease severity. Considering that IL-17F stimulation promotes neutrophil adhesion to the endothelium in a MAPK-dependent manner, it is attractive to speculate that this pathway may contribute to pathogenic immunothrombosis in concert with other molecular effectors.

100 Deals associated with Doramapimod

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External Link

KEGG	Wiki	ATC	Drug Bank
D03736	-	-	DB03044

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Crohn Disease	Phase 3	-	Boehringer Ingelheim GmbH	01 Oct 2001
Rheumatoid Arthritis	Phase 3	-	Boehringer Ingelheim GmbH	01 May 2001
Neoplasms	Phase 3	US	Boehringer Ingelheim GmbH	-
Psoriasis	Phase 3	-	C.H. Boehringer Sohn AG & Co. KG	-
Psoriasis	Phase 3	US	Boehringer Ingelheim GmbH	-
Plaque psoriasis	Preclinical	-	Boehringer Ingelheim GmbH	01 Jun 2001
Endotoxin Hyporesponsiveness	Preclinical	-	Boehringer Ingelheim GmbH	01 Feb 2000

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Phase l (AAAAI2002)	Not Applicable	-	-	BIRB 796 BS	(olkijiliua) = mild, reversible, clinically non-significant rise htzlihzzlz (coexlcqdpi ) View more	Positive	01 Mar 2002