MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MEK2 inhibitors(Dual specificity mitogen-activated protein kinase kinase 2 inhibitors)

Therapeutic Areas

Infectious Diseases

Active Indication

Bacterial Infections

Inactive Indication

Breast CancerColonic CancerNon-Small Cell Lung Cancer+ [1]

Originator Organization

Pfizer Inc.

Active Organization

University of Münster

Inactive Organization

Pfizer Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC17H14ClF2IN2O2

InChIKeyGFMMXOIFOQCCGU-UHFFFAOYSA-N

CAS Registry212631-79-3

Clinical Trials associated with CI-1040

NCT00033384 / CompletedPhase 2IIT

A Multicenter Phase 2 Study of CI-1040 In Patients With Advanced Nonsmall-Cell Lung Cancer, Breast Cancer, Colon Cancer Or Pancreatic Cancer

RATIONALE: CI-1040 may stop the growth of tumors by blocking the enzymes necessary for cancer cell growth and by stopping blood flow to the tumor.
PURPOSE: Phase II trial to study the effectiveness of CI-1040 in treating patients who have metastatic or unresectable breast, colon, pancreatic, or non-small cell lung cancer.

Start Date01 Feb 2002

Sponsor / Collaborator

The University of Alabama at Birmingham

[+1]

NCT00034827 / CompletedPhase 2

A Multicenter Phase 2 Study of CI-1040 in Patients With Advanced Nonsmall-Cell Lung Cancer, Breast Cancer, Colon Cancer, or Pancreatic Cancer

CI-1040 is an experimental drug that is being tested in patients who have advanced colorectal and lung cancer who failed no more than one prior chemotherapy regimen, breast cancer who have failed no more than 2 prior regimens and in patients with pancreatic cancer who have received no prior chemotherapy. CI-1040 is taken orally twice daily with meals. Patients are required to have blood tests periodically while receiving treatment and will be monitored closely throughout the trial for possible side effects and for response.

Start Date01 Jan 2002

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with CI-1040

100 Translational Medicine associated with CI-1040

100 Patents (Medical) associated with CI-1040

240

Literatures (Medical) associated with CI-1040

03 May 2024·Brain Communications

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition

Article

Author: Smith, Rachael A ; Loeb, Jeffrey A ; Maharathi, Biswajit ; Butler, Mitchell P ; Mir, Fozia

AbstractInterictal spikes are electroencephalographic discharges that occur at or near brain regions that produce epileptic seizures. While their role in generating seizures is not well understood, spikes have profound effects on cognition and behaviour, depending on where and when they occur. We previously demonstrated that spiking areas of human neocortex show sustained MAPK activation in superficial cortical Layers I–III and are associated with microlesions in deeper cortical areas characterized by reduced neuronal nuclear protein staining and increased microglial infiltration. Based on these findings, we chose to investigate additional neuronal populations within microlesions, specifically inhibitory interneurons. Additionally, we hypothesized that spiking would be sufficient to induce similar cytoarchitectonic changes within the rat cortex and that inhibition of MAPK signalling, using a MAP2K inhibitor, would not only inhibit spike formation but also reduce these cytoarchitectonic changes and improve behavioural outcomes. To test these hypotheses, we analysed tissue samples from 16 patients with intractable epilepsy who required cortical resections. We also utilized a tetanus toxin-induced animal model of interictal spiking, designed to produce spikes without seizures in male Sprague–Dawley rats. Rats were fitted with epidural electrodes, to permit EEG recording for the duration of the study, and automated algorithms were implemented to quantify spikes. After 6 months, animals were sacrificed to assess the effects of chronic spiking on cortical cytoarchitecture. Here, we show that microlesions may promote excitability due to a significant reduction of inhibitory neurons that could be responsible for promoting interictal spikes in superficial layers. Similarly, we found that the induction of epileptic spikes in the rat model produced analogous changes, including reduced neuronal nuclear protein, calbindin and parvalbumin-positive neurons and increased microglia, suggesting that spikes are sufficient for inducing these cytoarchitectonic changes in humans. Finally, we implicated MAPK signalling as a driving force producing these pathological changes. Using CI-1040 to inhibit MAP2K, both acutely and after spikes developed, resulting in fewer interictal spikes, reduced microglial activation and less inhibitory neuron loss. Treated animals had significantly fewer high-amplitude, short-duration spikes, which correlated with improved spatial memory performance on the Barnes maze. Together, our results provide evidence for a cytoarchitectonic pathogenesis underlying epileptic cortex, which can be ameliorated through both early and delayed MAP2K inhibition. These findings highlight the potential role for CI-1040 as a pharmacological treatment that could prevent the development of epileptic activity and reduce cognitive impairment in both patients with epilepsy and those with non-epileptic spike-associated neurobehavioural disorders.

01 May 2024·Heliyon

Establishment and validation of a gene mutation-based risk model for predicting prognosis and therapy response in acute myeloid leukemia

Article

Author: Liu, Liping ; Cao, Rongxuan ; Wang, Lijuan ; Li, Teng ; Zhang, Hongling ; Liu, Jing ; Liu, Yun ; Zhang, Junying

BackgroundAcute myeloid leukemia (AML) is a malignant clonal proliferative disease of hematopoietic system. Despite tremendous progress in uncovering the AML genome, only a small number of mutations have been incorporated into risk stratification and used as therapeutic targets. In this research, we performed to construct a predictive prognosis risk model for AML patients according to gene mutations.MethodsNext-generation sequencing (NGS) technology was utilized to detect gene mutation from 118 patients. mRNA expression profiles and related clinical information were mined from TCGA and GEO databases. Consensus cluster analysis was applied to obtain molecular subtypes, and differences in clinicopathological features, prognosis, and immune microenvironment of different clusters were systematically compared. According to the differentially expressed genes (DEGs) between clusters, univariate and LASSO regression analysis were applied to identify gene signatures to build a prognostic risk model. Patients were classified into high-risk (HR) and low-risk (LR) groups according to the median risk score (RS). Differences in prognosis, immune profile, and therapeutic sensitivity between two groups were analyzed. The independent predictive value of RS was assessed and a nomogram was developed.ResultsNGS detected 24 mutated genes, with higher mutation frequencies in CBL (63 %) and SETBP1 (49 %). Two clusters exhibited different immune microenvironments and survival probability (p = 0.0056) were identified. A total of 444 DEGs were screened in two clusters, and a mutation-associated risk model was constructed, including MPO, HGF, SH2B3, SETBP1, HLA-DRB1, LGALS1, and KDM5B. Patients in LR had a superior survival time compared to HR. Predictive performance of this model was confirmed and the developed nomogram further improved the applicability of the risk model with the AUCs for predicting 1-, 3-, 5-year survival rate were 0.829, 0.81 and 0.811, respectively. HR cases were more sensitive to erlotinib, CI-1040, and AZD6244.ConclusionThese findings supplemented the understanding of gene mutations in AML, and constructed models had good application prospect to provide effective information for predicting prognosis and treatment response of AML.

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 CI-1040

External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	US	Pfizer Inc.	01 Jan 2002
Colonic Cancer	Phase 2	US	Pfizer Inc.	01 Jan 2002
Non-Small Cell Lung Cancer	Phase 2	US	Pfizer Inc.	01 Jan 2002
Pancreatic Cancer	Phase 2	US	Pfizer Inc.	01 Jan 2002
Bacterial Infections	Preclinical	DE	University of Münster	14 Jun 2018

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