CI-1040 / Pfizer - LARVOL DELTA

Exploring the prognostic value of T cell exhaustion and mitochondrial dysfunction related genes in breast cancer through bioinformatics analysis and RT-qPCR validation. (PubMed, Clin Exp Med) - "The accurate risk model stratified patients: high-risk correlated with suppressed immunity (p < 2.2e-16), elevated TIDE (p = 5.4e-14), and higher CI.1040 IC50 (cor = 0.63, p < 0.0001)...Risk score, age, race, N/M-stage were independent factors. Seven prognostic genes effectively predicted BRCA prognosis with independent prognostic factors."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • BCL2A1 • BRCA • CD74 • GZMB • IRF7 • MTHFD2 • PPP1R15A

The ATR inhibitor Elimusertib in Combination with Cisplatin in Patients with Advanced Solid Tumors: a California Cancer Consortium Phase I Trial (NCI10404). (PubMed, Cancer Res Commun) - "Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib PK was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted."

Journal • P1 data • Ataxia • Febrile Neutropenia • Hematological Disorders • Immunology • Movement Disorders • Neutropenia • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Primary Immunodeficiency • Solid Tumor • Thrombocytopenia • ATR

Targeting the MEK1/2 pathway to combat Staphylococcus aureus infection and inflammation in cystic fibrosis. (PubMed, mBio) - "Our previous studies demonstrated anti-inflammatory effects of several MEK1/2 inhibitor compounds, including PD0325901, CI-1040, and trametinib, in human phagocytes from PwCF and a murine S. aureus pulmonary infection model (M. This work also identifies host MEK2 as a specific target that can be modulated to reduce inflammation without impairing host defense against MRSA pulmonary infection. Results from this study can inform future human clinical trials to evaluate the ability of the MEK1/2 inhibitor compound ATR-002 to both combat S. aureus infections and reduce inflammation that accompanies these infections."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL8 • MAP2K1 • MAP2K2 • TLR2 • TNFA

Downstream Signaling Mediators of CXCL6-driven Synthesis of Collagen in Human Fibroblasts (ATS 2025) - "Doxycycline was used to induce CXCL6 expression and secretion in BJ13 cells. A panel of specific pathway inhibitors were added to cells, including SR11302 (AP1), MK2206 (AKT), SB203850 (p38), SP600125 (JNK), PD184352 (MEK), FASUDIL (ROCK/RHO), SLV2436 (MNK1/2), Omipalisib (mTOR/PI3K), Torin (mTOR), and Reparixin (CXCR1/2)... We identified that CXCL6 induces collagen production through multiple pathways including mTOR, p38, JNK and MEK. Targeting a combination of these pathways may be a potential therapeutic direction for IPF treatment."

Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CXCL6 • CXCR1 • SMAD3 • TGFB1

Cell Division Cycle 42 Improves Renal Functions, Fibrosis, Th1/Th17 Infiltration and Inflammation to Some Degree in Diabetic Nephropathy. (PubMed, Inflammation) - "However, the treatment of LY294002 and CI-1040 had limited effect on attenuating CDC42's functions on renal function and fibrotic markers. CDC42 improves renal functions, fibrosis, Th1/Th17 infiltration and inflammation to some degree in DN mice, these functions may be independent to AKT and ERK pathways."

IO biomarker • Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • CDC42 • IFNG • IL17A • IL1B • IL6 • TGFB1 • TNFA

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. (PubMed, Front Immunol) - "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)...Overall, 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."

Journal • Observational data • Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis • ICAM1 • IL17A • MAP2K1 • MAP2K2 • MAPK1 • MAPK3

SNHG14 promotes triple-negative breast cancer cell proliferation, invasion, and chemoresistance by regulating the ERK/MAPK signaling pathway. (PubMed, IUBMB Life) - "Compared with the DMSO group, the proliferation of Docetaxel-resistant MDA-MB-231 cells was decreased in Dabrafenib, PD184352, and FR180204 treatment groups. SNHG14 knockdown inhibits TNBC progression by regulating the ERK/MAPK signaling pathway, which provides evidence for SNHG14 as a potential target for TNBC therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • DDIT3 • FGFR4 • MKNK1 • PDGFRB • SNHG14

Equine Endothelial Cells Show Pro-Angiogenic Behaviours in Response to Fibroblast Growth Factor 2 but Not Vascular Endothelial Growth Factor A. (PubMed, Int J Mol Sci) - "Pharmacological inhibitors of FGF receptor 1 (FGFR1) (SU5402) or mitogen-activated protein kinase (MEK) (PD184352) blocked FGF2-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and functional responses, suggesting that these are dependent on FGFR1/MEK-ERK signalling...These results suggest a predominant role for FGF2 versus VEGF-A in controlling the angiogenic functions of equine ECs. Collectively, our novel data provide a sound basis for studying angiogenic processes in horses and lay the foundations for comparative studies of EC biology in horses versus humans."

Journal • FGF2 • FGFR1 • FLT1 • KDR • VEGFA

Establishment and validation of a gene mutation-based risk model for predicting prognosis and therapy response in acute myeloid leukemia. (PubMed, Heliyon) - "HR cases were more sensitive to erlotinib, CI-1040, and AZD6244. These 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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HLA-DRB1 • KDM5B • LGALS1 • SETBP1 • SH2B3

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition. (PubMed, Brain Commun) - "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."

Journal • Alzheimer's Disease • Behavior Disorders • CNS Disorders • Cognitive Disorders • Epilepsy • Infectious Disease • Psychiatry • Tetanus • CALB1

Identification and validation of a glycosyltransferase gene signature as a novel prognostic model for lung adenocarcinoma. (PubMed, Heliyon) - "We identified potential therapeutic drugs, including the MEK inhibitor (PD-184352)...We identified a distinct LUAD GT gene signature, and these differentially expressed mRNAs could serve as valuable prognostic biomarkers and therapeutic targets. Furthermore, we experimentally validated their expression levels and identified potential therapeutic agents."

Gene Signature • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GALNT2 • PLOD2 • POMK

MEK1/2 inhibition decreases pro-inflammatory responses in macrophages from people with cystic fibrosis and mitigates severity of illness in experimental murine methicillin-resistant Staphylococcus aureus infection. (PubMed, Front Cell Infect Microbiol) - "Here we examined the immunomodulatory properties of MEK1/2 inhibitor compounds PD0325901, trametinib, and CI-1040 on CF innate immune cells. Wild-type mice treated with PD0325901 had significant reduction in neutrophil-mediated inflammation compared to vehicle treatment groups, with preserved clearance of bacteria in lung, liver, or spleen 1 day after infection in either wild-type or CF mouse models. In summary, this study provides the first data evaluating the therapeutic potential of MEK1/2 inhibitor to modulate CF immune cells and demonstrates that MEK1/2 inhibitors diminish pro-inflammatory responses without impairing host defense mechanisms required for acute pathogen clearance."

Journal • Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • MAP2K2

Qing Yan Li Ge Tang Induces Apoptosis in Human OEC-M1 Oral Cancer Cells. (PubMed, Altern Ther Health Med) - "Additionally, QYLGT-activated c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-kappa B (NF-κB), and the related inhibitors, including SP600125, PD184352, SB202190, and Bay11-7082, were used to confirm which signaling was involved in QYLGT-induced apoptosis. Moreover, only Bay11-7082, the NF-κB inhibitor, could suppress QYLGT-induced the release of cytokeratin 18 fragments from OEC-M1 cells. QYLGT induced apoptosis in OEC-M1 cells via the NF-κB pathway."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • CASP3 • CASP8 • CASP9 • KRT18 • MAPK8

Role of MEK1/2 pathway in regulating toll-like receptor 2–dependent pro-inflammatory responses (NACFC 2023) - "Macrophage cultures were stimulated with toll-like receptor (TLR)2 agonists Pam3CSK4 or FSL1 with addition of vehicle or one of three MEK1/2 inhibitor compounds (PD0325901, Trametinib, CI-1040) for 4 hours. Inhibition of the MEK1/2 pathway in human macrophages from PwCF reduces pro-inflammatory responses to TLR2 stimulation. Results from A549 KO cells indicate that MEK1 has a critical regulatory role to restrain the pro-inflammatory response to TLR2 stimulation, whereas KO or loss of MEK2 is able to dampen the pro-inflammatory response. This paradigm suggests that selective inhibition of MEK2 may be a preferred strategy to reduce the pro-inflammatory response."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • IL1B • MAP2K1 • MAP2K2 • TLR2

Crocin Combined With Cisplatin Regulates Proliferation, Apoptosis And Emt Of Gastric Cancer Cells Via The Fgfr3/Mapk/Erk Pathway In Vitro And In Vivo. (PubMed, Curr Cancer Drug Targets) - "Our results showed that up-regulation of FGFR3 reversed the inhibitory effect of crocin+DDP on the MAPK/ERK signaling pathway. Still, this effect could be counteracted by PD184352, which simultaneously regulated the proliferation, apoptosis, and EMT of AGS cells. In conclusion, crocin, combined with DDP, inhibits proliferation, apoptosis, and EMT of GC through the FRFR3/MAPK/ERK pathway."

Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR3

Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers. (PubMed, Front Pharmacol) - "A midazolam microdose was applied to quantify CYP3A4 activity...The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin...In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CYP3A4

PD184352 exerts anti-inflammatory and antioxidant effects by promoting activation of the Nrf2/HO-1 axis. (PubMed, Biochem Pharmacol) - "Finally, the anti-inflammatory and antioxidant effects of PD184352 were shown to be partially dependent on Nrf2 activation. Our study reveals the potential role of PD184352 as an antioxidant and provides a new strategy for OA treatment."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • IL1B • NFE2L2

Dysregulation of Mitochondrial Dynamics via Dynamin-Related Protein 1 Implicated in Dedifferentiated Liposarcoma (SSO 2023) - "Doxorubicin was given in combination to assess for chemo-sensitization. DRP1 expression and activation are a hallmark of DD LPS. Pharmacologic inhibition of DRP1 by Mdivi-1 or PD184352 in vitro promotes an elongated mitochondrial morphology, reduces cell growth and enhances chemosensitivity. Further investigation into the dysregulation of mitochondrial dynamics may reveal a novel treatment strategy to overcome chemoresistance."

Liposarcoma • Oncology • Sarcoma • Solid Tumor

Sulforaphane attenuates cancer cell-induced atrophy of C2C12 myotubes. (PubMed, Am J Physiol Cell Physiol) - "To determine whether SFN could attenuate wasting induced by cancer cells, myotubes were co-cultured with or without Colon-26 (C-26) cancer cells for 48 h and treated with 5-fluorouracil (5-FU, 5 µM) or vehicle (DMSO). Co-administration of Nrf2 inhibitors (ML-385) or MEK inhibitors (PD184352) revealed SFN's attenuation of atrophy was blocked by ERK inhibition. These data support the chemoprotective and antioxidative function of SFN in myotubes, highlighting its therapeutic potential for cancer-related muscle wasting."

Journal • Cachexia • Colon Cancer • Oncology

GPR120-ERK1-Srebp1c signaling pathway regulates long-chain polyunsaturated fatty acids biosynthesis in marine teleost Siganus canaliculatus. (PubMed, Comp Biochem Physiol B Biochem Mol Biol) - "Transcriptome analysis of the treated SCHL cells showed significantly lower mRNA levels of genes encoding extracellular signal-regulated kinase 1 (ERK1), AMP-activated protein kinase (AMPKα2), target of rapamycin (TORC2) and Srebp1c, suggesting that these proteins are potentially involved in the GRP120 signaling pathway. CI-1040-treated cells showed significantly higher DHA content, but the other treatment groups (except PD98059) showed significantly lower DHA content. These results indicate that the GPR120-ERK1-Srebp1c signaling pathway regulates rabbitfish LC-PUFA biosynthesis, representing a novel regulatory mechanism in vertebrates."

Journal

Masitinib analogues with the N-methylpiperazine group replaced - A new hope for the development of anti-COVID-19 drugs. (PubMed, J King Saud Univ Sci) - "The filtered analogues were subjected to molecular docking studies which revealed that the analogues with substituents methylamine in M10 (CID10409602), morpholine in M23 (CID59789397) and 4-methylmorpholine in M32 (CID143003625) have a stronger affinity to the drug receptor compared to masitinib. These structural alterations can help explain the inhibitory mechanisms of these analogues against the target enzyme. Thus, our studies provide avenues for the design of new masitinib analogues as the SARS-CoV-2 M inhibitors."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Asthma • CNS Disorders • Immunology • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Oncology • Pulmonary Disease • Respiratory Diseases

IL-33 induces granzyme C expression in murine mast cells via an MSK1/2-CREB dependent pathway. (PubMed, Biosci Rep) - "These increases in both granzyme C mRNA and protein were blocked by a combination of the p38alpha/beta MAPK inhibitor VX745 and the MEK1/2 inhibitor PD184352, which blocks the activation of ERK1/2. The promoter for granzyme C contains a potential CREB binding site. Bone marrow derived mast cells from either MSK1/2 double knockout or CREB Ser133Ala knockin mice were unable to upregulate granzyme C. Together these results indicate that IL-33 induced granzyme C expression in mast cells is regulated by an MSK1/2-CREB dependent pathway."

Journal • Preclinical • Oncology • GZMB • IL33 • MAPK14

Anti-inflammatory effects of MEK1/2 inhibitors on cystic fibrosis macrophages (NACFC 2022) - "To determine the effect of MEK1/2inhibitor compounds on CF macrophage pro-inflammatory responses,macrophages were stimulated with 50 ng/mL of P. aeruginosaLPS with addition of vehicle (dimethyl sulfoxide), 0.5 mM PD0325901, 10 mM CI-1040, or 0.5 mM GSK1120212 for 4 hours. MEK1/2 inhibitor compounds significantly decrease pro-inflammatory responses of human CF macrophages after stimulation withLPS, but treatment of macrophages with MEK1/2 inhibitor compounds didnot alter phagocytosis or phagosome acidification of pHrodo red –labeled bioparticles. These data support the hypothesis that MEK1/2 inhibitorcompounds can be used to reduce detrimental inflammation withoutimpairing host defense mechanisms. Future studies will evaluate theeffects of MEK1/2 inhibitor compounds on the effector functions of CFneutrophils and on the in vivo response to infection."

Acute Lung Injury • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCL8 • IL1B

A Three-Gene Signature for Predicting the Prognosis of Patients Treated with Transarterial Chemoembolization (TACE) and Identification of PD-184352 as a Potential Drug to Reverse Nonresponse to TACE. (PubMed, J Oncol) - "We constructed a TACE-specific three-gene signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment. PD-184352 might have potential as a drug to improve TACE efficacy."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • HIF1A • HMOX1 • SERPINE1

Direct Targeting of the Raf-MEK-ERK Signaling Cascade Inhibits Neuroblastoma Growth. (PubMed, Curr Oncol) - "Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB."

Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor