MAPK

GSK143 dihydrochloride is an orally active and highly selective inhibitor of spleen tyrosine kinase (SYK), exhibiting a pIC₅₀ of 7.5. It also inhibits phosphorylated ERK (pErk) with a pIC₅₀ of 7.1, indicating its ability to modulate downstream signaling pathways involved in immune responses. In preclinical models, GSK143 dihydrochloride effectively reduces inflammation and prevents the recruitment of immune cells to the intestinal muscularis, highlighting its potential as a therapeutic agent for inflammatory diseases, particularly those involving the gastrointestinal tract.

Deltonin is a steroidal saponin isolated from *Dioscorea zingiberensis*, exhibiting notable antitumor activity. It exerts its effects by inhibiting the activation of key survival and proliferation pathways, specifically ERK1/2 and AKT signaling. Through this dual inhibition, Deltonin suppresses tumor cell growth and promotes apoptosis, making it a promising candidate for further investigation in cancer research and therapeutic development.

Lobeglitazone is a novel thiazolidinedione-class compound and an orally active dual agonist of peroxisome proliferator-activated receptors (PPARs), with EC₅₀ values of 137.4 nM for PPARγ and 546.3 nM for PPARα. In addition to its metabolic effects, Lobeglitazone functions as an inhibitor of multiple pro-inflammatory and pro-fibrotic signaling pathways, including ERK, JNK, Smad, and NF-κB. Lobeglitazone exhibits a broad range of pharmacological activities, including anti-inflammatory, anti-diabetic, anti-fibrotic, and anti-atherosclerotic effects. These properties make it a promising candidate for therapeutic research in metabolic syndrome, type 2 diabetes, cardiovascular disease, and fibrosis-related conditions.

Enniatin B1 is a mycotoxin produced by Fusarium species, known for its diverse bioactivities. It functions as a moderate inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), with an IC₅₀ of 73 μM in assays using rat liver microsomes, implicating a role in lipid metabolism modulation. Enniatin B1 is capable of crossing the blood-brain barrier, suggesting potential effects on central nervous system function. It also decreases the activation of ERK1/2 (p44/p42 MAPK) and moderately inhibits TNF-α-induced NF-κB activation, indicating anti-inflammatory and cell signaling modulatory properties.

MY-673 is a colchicine binding site inhibitor (CBSI) that disrupts microtubule dynamics by inhibiting tubulin polymerization. In addition to its antimitotic effects, MY-673 suppresses the ERK signaling pathway, which leads to modulation of SMAD4 protein expression within the TGF-β/SMAD signaling axis. These combined actions result in potent inhibition of cancer cell proliferation and migration, and the induction of apoptosis, both in vitro and in vivo. MY-673 holds promise as a therapeutic candidate for targeting cancers driven by aberrant microtubule dynamics and dysregulated TGF-β/ERK signaling.

MAPK-IN-1 (Compound 2) is an inhibitor of the MAPK signaling pathway with demonstrated neuroprotective and anti-neuroinflammatory properties. It also exhibits acetylcholinesterase (AChE) inhibitory activity, with an IC₅₀ of 23.84 μM, contributing to enhanced cholinergic signaling. These combined actions make MAPK-IN-1 a promising candidate for research in Alzheimer's disease and other neurodegenerative disorders, where modulation of MAPK signaling and cholinergic function are of therapeutic interest.

Rineterkib hydrochloride (compound B) is an orally bioavailable inhibitor of ERK1 and ERK2, developed for the treatment of proliferative diseases driven by activating mutations in the MAPK signaling pathway. It exhibits potent antitumor activity, particularly in cancers harboring KRAS or BRAF mutations.

Serum thymic factor acetate (Thymulin acetate) is the acetate salt form of thymulin, a zinc-dependent nonapeptide hormone produced by thymic epithelial cells. It functions as an immunomodulatory and neuroendocrine regulator with broad biological activity. Thymulin acetate stimulates hormone release from the pituitary gland, exhibiting hypophysiotropic effects, and modulates immune responses. It has demonstrated protective effects against Cephaloridine-induced nephrotoxicity in rats by inhibiting ERK pathway activation. Additionally, thymulin acetate displays anti-diabetic, anti-inflammatory, and analgesic properties.

4′-Demethylnobiletin is a bioactive metabolite derived from citrus polymethoxyflavones, known for its neuroprotective and cognition-enhancing properties. It activates the PKA/ERK/CREB signaling pathway and enhances CRE (cAMP response element)-mediated transcription in hippocampal neurons, processes essential for synaptic plasticity and memory formation. Additionally, 4′-Demethylnobiletin reverses memory impairment caused by NMDA receptor antagonism by stimulating ERK signaling, highlighting its therapeutic potential for neurodegenerative diseases and cognitive dysfunction.

6-Hydroxyflavone is an orally active flavonoid with diverse pharmacological properties. It exhibits anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) production and also promotes osteoblast differentiation through activation of the AKT, ERK1/2, and JNK signaling pathways, supporting its role in bone health. Additionally, 6-Hydroxyflavone inhibits the glycosylation of bovine hemoglobin (BHb), suggesting potential in managing glycation-related complications. It demonstrates kidney-protective effects and modulates GABAergic neurotransmission by enhancing GABA-induced currents via the benzodiazepine binding sites on GABAA receptors

CLH304a (compound 14) is a selective and noncompetitive negative allosteric modulator (NAM) of the GABA$_B$ receptor. It specifically targets the heptahelical domain of the GB2 subunit, inhibiting receptor activity with inverse agonist properties. CLH304a reduces GABA-induced inositol trisphosphate (IP₃) production with an IC₅₀ of 37.9 μM and does not affect other Class C GPCRs, including mGluR1, mGluR2, and mGluR5, indicating high selectivity. Additionally, CLH304a inhibits Baclofen-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA$_B$ receptors, further supporting its function as a negative modulator. This compound is a valuable tool for investigating GABA$_B$ receptor function and holds potential for therapeutic research in neurological disorders involving GABAergic signaling dysregulation.

Anti-inflammatory agent 35 (compound 5a27) is an orally active curcumin analogue that exhibits potent anti-inflammatory activity. It exerts its effects by blocking mitogen-activated protein kinase (MAPK) signaling and inhibiting the nuclear translocation of the NF-κB subunit p65, thereby suppressing key inflammatory pathways. Additionally, compound 5a27 reduces neutrophil infiltration and the production of pro-inflammatory cytokines. In vivo, it significantly attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI), highlighting its potential as a therapeutic candidate for inflammatory and respiratory disorders.

HA-1004 is a selective and multifunctional inhibitor of cyclic nucleotide-dependent protein kinases, including protein kinase A (PKA) and cyclic GMP-dependent protein kinase (PKG). It regulates key second messenger pathways involving cyclic AMP and cyclic GMP and has broad pharmacological effects. HA-1004 inhibits lipolysis and induces vascular smooth muscle relaxation, acting as a vasodilator. It also functions as a calcium antagonist, contributing to its ability to suppress contraction in rabbit aortic strips. In neurological models, HA-1004 has been shown to antagonize ERK and tyrosine hydroxylase (TH) phosphorylation in morphine abstinence rat models, suggesting potential relevance in addiction and neurochemical regulation. Its diverse actions make it a valuable tool for studying cardiovascular, metabolic, and neurobiological processes.

Firazorexton hydrate (TAK-994) is an orally active, brain-penetrant selective agonist of the orexin type 2 receptor (OX2R). It effectively promotes wakefulness by stimulating OX2R signaling, which plays a critical role in regulating the sleep–wake cycle. In preclinical studies, Firazorexton hydrate has demonstrated the ability to alleviate narcolepsy-like symptoms in mouse models, making it a promising therapeutic candidate for sleep disorders such as narcolepsy and excessive daytime sleepiness.

Tenuifoliside A is a bioactive compound isolated from *Polygala tenuifolia*, known for its anti-apoptotic and antidepressant-like effects. It exerts neurotrophic activity by promoting cell proliferation through activation of the ERK/CREB/BDNF signaling pathway in C6 glial cells. These properties highlight its potential as a neuroprotective and mood-regulating agent, making it a promising candidate for research in depression and neurodegenerative disorders.

Brophenexin (compound 8) is a potent inhibitor of the interaction interface between NMDA receptors (NMDAR) and TRPM4 channels, exhibiting significant neuroprotective activity. It prevents NMDA-induced excitotoxicity, including cell death and mitochondrial dysfunction in hippocampal neurons, with an IC₅₀ of 2.1 μM. In vivo, Brophenexin protects against brain damage in mice subjected to middle cerebral artery occlusion (MCAO) and preserves retinal ganglion cells from NMDA-induced degeneration. These findings support its potential as a therapeutic agent for neurodegenerative diseases and ischemic brain injury.

EtDO-P4 is a potent nanomolar inhibitor of glycosphingolipid (GSL) synthesis that disrupts lipid-mediated signaling in cancer cells. It effectively suppresses activation of the EGFR-induced ERK pathway as well as multiple receptor tyrosine kinases (RTKs), impairing key proliferative and survival signals. EtDO-P4 has demonstrated anticancer potential across various tumor types, including Burkitt’s lymphoma, making it a valuable compound for studying GSL-dependent oncogenic signaling and for the development of targeted cancer therapies.

ML192 is a selective antagonist of G protein-coupled receptor 55 (GPR55), effectively inhibiting GPR55-mediated signaling pathways. It blocks β-arrestin trafficking, suppresses ERK1/2 phosphorylation, and prevents PKCβII translocation, thereby interfering with downstream cellular responses. ML192 is a valuable tool for studying the physiological and pathological roles of GPR55 in processes such as inflammation, pain, cancer, and metabolic regulation.

Isoprocurcumenol is a guaiane-type sesquiterpene isolated from *Curcuma comosa* with notable bioactivity in epidermal growth factor receptor (EGFR) signaling. It activates EGFR and enhances downstream phosphorylation of ERK and AKT, key mediators of cell survival and proliferation pathways. As a result, isoprocurcumenol promotes keratinocyte proliferation, suggesting potential applications in skin regeneration, wound healing, and dermatological research.

Gamma-linolenic acid (γ-linolenic acid, GLA) is an orally active omega-6 unsaturated fatty acid with broad pharmacological activities. It exhibits anti-inflammatory effects by inhibiting the NF-κB signaling pathway and suppressing the phosphorylation of ERK1/2 and JNK, key mediators of inflammatory responses. GLA also induces apoptosis in cancer cells, contributing to its anticancer potential. Additionally, it possesses antioxidant properties and has been shown to improve memory function, suggesting neuroprotective benefits. These multifunctional effects position gamma-linolenic acid as a promising compound for research in inflammation, oncology, and neurological disorders.

Lysophosphatidylcholines (LPCs) are orally active lysolipids and key components of oxidized low-density lipoprotein (oxLDL). They are bioactive molecules known to induce cellular injury, promote the production of pro-inflammatory cytokines such as interleukin-1β (IL-1β), and trigger apoptosis. LPCs play a significant role in the pathophysiology of various inflammatory conditions and have been implicated in the progression of sepsis by amplifying inflammatory responses. Due to these properties, LPCs are actively studied in the context of inflammation, cardiovascular disease, and sepsis-related research.

ASN007 (also known as ERK-IN-3) is a potent, orally active inhibitor of extracellular signal-regulated kinases ERK1 and ERK2, exhibiting low single-digit nanomolar IC₅₀ values. By directly targeting ERK, ASN007 effectively disrupts the MAPK/ERK signaling pathway, which is frequently activated in RAS-mutant cancers. It serves as a valuable therapeutic candidate and research tool for studying and potentially treating malignancies driven by aberrant RAS signaling, including colorectal, pancreatic, and non-small cell lung cancers.

Pamoic acid (Embonic acid) is a potent agonist of G protein-coupled receptor 35 (GPR35), with an EC₅₀ of 79 nM. Activation of GPR35 by pamoic acid is associated with both neuroprotective and anti-inflammatory effects, making it a valuable compound for research into neurological disorders and inflammatory diseases. Its pharmacological profile suggests potential therapeutic applications in conditions where GPR35-mediated signaling plays a regulatory role.

LUNA18 is an orally bioavailable cyclic peptide that functions as a dual inhibitor of KRAS and ERK signaling pathways. It disrupts the interaction between RAS and guanine nucleotide exchange factors (GEFs), effectively inhibiting RAS activation and downstream signaling. In RAS-mutated cancer cells, LUNA18 reduces cell proliferation while modulating key signaling nodes, including phosphorylation of ERK and AKT. In preclinical studies, LUNA18 demonstrates potent anticancer activity, particularly in xenograft models, by blocking RAS-driven tumor growth. It shows significant cellular efficacy against cancer cell lines harboring KRAS mutations, including colon, gastric, pancreatic, and non-small cell lung cancers, highlighting its therapeutic potential as a targeted agent for RAS-driven malignancies.

Inflachromene is a microglial inhibitor that exerts anti-inflammatory effects by directly binding to high mobility group box proteins HMGB1 and HMGB2. Through this interaction, it effectively downregulates the proinflammatory activities of HMGB proteins, leading to reduced microglial activation and neuronal damage. Inflachromene holds promise as a therapeutic candidate for the treatment of neuroinflammatory disorders, including neurodegenerative diseases and central nervous system injuries.

mSIRK (G-Protein βγ Binding Peptide) is a cell-permeable peptide that functions as an activator of ERK1/2 signaling, with an EC₅₀ of 2.5–5 μM. It disrupts the interaction between the G-protein α and βγ subunits, promoting dissociation of the α subunit independently of nucleotide exchange. By modulating G-protein signaling, mSIRK enables selective activation of downstream pathways, such as ERK1/2, and serves as a valuable tool for studying G-protein–mediated signal transduction and ERK pathway activation.

SY-LB-35 is a potent agonist of bone morphogenetic protein (BMP) receptors, capable of activating both canonical and non-canonical signaling pathways. In the C2C12 myoblast cell line, SY-LB-35 significantly enhances cell proliferation and viability, promoting cell cycle progression by increasing the proportion of cells in the S and G2/M phases. Mechanistically, it activates the canonical Smad pathway as well as non-canonical PI3K/Akt, ERK, p38, and JNK signaling cascades. These properties make SY-LB-35 a valuable tool for studying BMP-related cellular processes and a potential therapeutic candidate for tissue regeneration and muscle repair.

ASTX029 (Example 1) is a highly potent dual inhibitor of ERK1 and ERK2, with an IC₅₀ of 2.7 nM. By directly targeting both isoforms of extracellular signal-regulated kinase, ASTX029 effectively blocks downstream MAPK/ERK signaling, a pathway frequently dysregulated in cancer. It exhibits strong anticancer activity and is being investigated as a therapeutic candidate for malignancies driven by aberrant RAS-RAF-MEK-ERK signaling.

Broussonin E is a phenolic compound with demonstrated anti-inflammatory properties. It exerts its effects by modulating macrophage activation, specifically through inhibition of the ERK and p38 MAPK signaling pathways while enhancing the JAK2–STAT3 pathway. This dual regulatory mechanism helps suppress pro-inflammatory responses and supports immune homeostasis. Broussonin E is a promising candidate for research into inflammation-related diseases, including atherosclerosis and other chronic inflammatory conditions.

Gypenoside L is a bioactive saponin isolated from *Gynostemma pentaphyllum*, known for its diverse pharmacological properties. It induces cellular senescence by increasing senescence-associated β-galactosidase (SA-β-gal) activity and promoting the secretion of senescence-associated secretory phenotype (SASP) cytokines. Mechanistically, Gypenoside L activates the p38 and ERK MAPK pathways as well as the NF-κB signaling pathway to trigger senescence. In addition to its pro-senescent effects, Gypenoside L exhibits notable anti-tumor and anti-inflammatory activities, making it a promising compound for research in cancer biology and inflammation-related diseases.

HS-276 is an orally bioavailable, potent, and highly selective inhibitor of transforming growth factor-β–activated kinase 1 (TAK1), with a Kᵢ of 2.5 nM. It exhibits strong inhibition of TAK1 and moderate activity against a panel of other kinases, including CLK2, GCK, ULK2, MAP4K5, IRAK1, NUAK, CSNK1G2, CAMKKβ-1, and MLK1, with respective IC₅₀ values ranging from 8.25 to 5585 nM. HS-276 is a valuable tool for investigating TAK1-mediated signaling pathways and holds therapeutic potential for inflammatory conditions such as rheumatoid arthritis (RA).

AR420626 is a selective agonist of free fatty acid receptor 3 (FFAR3, also known as GPR41), with an IC₅₀ of 117 nM. It demonstrates anti-inflammatory, antitumor, and antidiabetic activities. AR420626 improves neurogenic diarrhea by modulating neural pathways mediated by nicotinic acetylcholine receptors (nAChRs). In cancer models, it suppresses the growth of HepG2 xenografts and inhibits hepatoma cell proliferation through apoptosis induction. Additionally, AR420626 mitigates allergic asthma and eczema and enhances glucose uptake by activating FFAR3-mediated Ca²⁺ signaling, offering potential therapeutic benefits in metabolic disorders such as diabetes.

PROTAC SOS1 Degrader-1 (TFA) is a potent PROTAC molecule targeting SOS1, with a DC₅₀ of 98.4 nM. It exhibits antiproliferative activity in cancer cells harboring various KRAS mutations and demonstrates antitumor efficacy with low toxicity, making it a promising candidate for targeted cancer therapy research.

SS47 TFA is a PROTAC-based degrader targeting hematopoietic progenitor kinase 1 (HPK1), an immunosuppressive regulatory kinase. It induces proteasome-mediated degradation of HPK1 and significantly enhances the antitumor efficacy of BCMA CAR-T cell therapy in vivo. In addition to its biological function, SS47 TFA is also a click chemistry reagent containing an alkyne group, allowing it to participate in copper-catalyzed azide–alkyne cycloaddition (CuAAC) with azide-functionalized molecules. This dual functionality makes SS47 TFA a valuable tool in both cancer immunotherapy research and chemical biology applications.

FOSL1 Degrader 1 (4) is a potent T-5224-based PROTAC that selectively degrades FOSL1 (AP-1), suppressing cancer stemness gene expression in head and neck squamous cell carcinoma (HNSCC). It effectively inhibits tumor growth and eliminates cancer stem cells, showing 30–100 times greater efficacy than T-5224.

MS432 is a first-in-class, highly selective PROTAC degrader targeting MEK1 and MEK2, based on PD0325901 and a von Hippel-Lindau (VHL) E3 ligase ligand. It demonstrates favorable plasma exposure in mice and induces MEK1 and MEK2 degradation in HT29 cells with DC₅₀ values of 31 nM and 17 nM, respectively.

(3S)-Tanzisertib hydrochloride is a selective inhibitor of c-Jun N-terminal kinases (JNK), demonstrating IC50 values of 61, 7, and 6 nM for JNK1, JNK2, and JNK3, respectively. This compound also exhibits inhibition of ERK1, p38α, and EGFR with IC50 values of 0.48, 3.4, and 0.38 μM, respectively. (3S)-Tanzisertib hydrochloride effectively reduces LPS-induced TNFα production in an acute rat pharmacokinetic-pharmacodynamic model, making it a valuable tool in idiopathic pulmonary fibrosis research and other inflammatory disease studies.

Erufosine is a potent inhibitor of the PI3K/Akt and Ras/Raf/MAPK signaling pathways. It demonstrates significant cytotoxic activity against breast cancer cell lines, specifically MCF-7 and MDA-MB-231, with IC50 values of 40.95 μM and 40.8 μM, respectively. By reducing the phosphorylation levels of PI3K (p85), Akt (PKB), and cRaf, Erufosine serves as a valuable tool in the research of breast cancer and myeloid leukemia.

Asperosaponin V is an indirect modulator of key signaling pathways, including PI3K/AKT, BMP-2/p38, and ERK 1/2. This compound stimulates the proliferation of marrow stromal cells and promotes differentiation into osteoblasts, making it valuable for studying bone metabolism. Asperosaponin V holds potential for applications in osteoporosis research and fracture healing studies.

Licochalcone E is a flavonoid compound that functions as a p38 MAPK inhibitor. It effectively inhibits the transcriptional activities of NF-κB and AP-1 by disrupting AKT and MAPK activation pathways. This compound is valuable for research focused on inflammation, cancer, and signal transduction pathways, offering insights into cellular mechanisms influenced by MAPK signaling.

H-Ile-Lys-Val-Ala-Val-OH is a potent activator of the MAPK/ERK1/2 and PI3K/Akt signaling pathways. This compound enhances cell adhesion, promotes neurite outgrowth, and supports tumor growth. It is particularly effective in stimulating the proliferation of bone marrow-derived mesenchymal stem cells (BMMSCs), making it valuable for research applications in cell biology and regenerative medicine.

AS1940477 is an orally active inhibitor of the p38 MAPK pathway, targeting both the p38α and p38β isoforms. It effectively reduces the production of pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, in human synovial interstitial cells and relevant animal models of inflammation. This compound is a valuable tool for research aimed at understanding and treating inflammatory diseases.

PF-06745013 is a selective inhibitor of MAP4K4, exhibiting an IC50 of 0.4 nM. This compound is distinguished by its lack of time-dependent inhibition risk for CYP3A4 and demonstrates non-ATP competitive activity. PF-06745013 has potential applications in the study of inflammatory diseases, including diabetes and cancer, making it a valuable tool in related research.

rel-Talmapimod hydrochloride is a selective inhibitor of p38α MAPK, exhibiting an IC50 of 9 nM. By targeting the p38α MAPK pathway, rel-Talmapimod hydrochloride effectively inhibits the secretion of pro-inflammatory factors, including TNFα, IL-1β, IL-6, and VEGF, while also blocking angiogenesis and osteoclast activation. This compound has demonstrated the ability to inhibit the proliferation of multiple myeloma cells and induce apoptosis. It is suitable for research applications involving various hematological malignancies, such as multiple myeloma and myelodysplastic syndrome.

R-03201195 is a highly selective inhibitor of p38 MAP kinase, demonstrating an IC50 of 0.7 nM for p38α. It effectively inhibits TNF-α production in THP-1 cells and IL-1β in human whole blood, with IC50 values of 0.25 nM and 0.57 nM, respectively. This reagent is valuable for research applications in inflammatory diseases, particularly rheumatoid arthritis.

PHI-501 is a dual inhibitor targeting RAF and DDR pathways. It demonstrates potent anti-proliferative effects in melanoma cell lines, effectively inhibiting colony formation in drug-resistant cells. PHI-501 disrupts ERK and AKT phosphorylation and downregulates key gene sets associated with TNFA-NFKB, IL6-JAK-STAT3, and KRAS signaling pathways, as well as pathways involved in epithelial-mesenchymal transition. In vivo studies show significant anti-tumor efficacy in the SK-MEL3DR xenograft model, making PHI-501 valuable for research on drug resistance in melanoma.

BMS-751324 is a selective inhibitor of p38α MAPK, a key regulator in the inflammatory response pathway. This compound demonstrates significant anti-inflammatory effects, as evidenced by its ability to reduce foot swelling and inhibit LPS-induced TNFα production in an arthritic rat model. BMS-751324 is suitable for research applications focused on inflammation, arthritis, and related pathways.

P38α-IN-10 is a selective inhibitor of p38α with an IC₅₀ of 230 nM. It effectively suppresses TNF production induced by lipopolysaccharide (LPS), making it a valuable tool for research into inflammatory responses. This compound is particularly relevant for studying conditions such as rheumatoid arthritis and septic shock, contributing to a deeper understanding of their underlying mechanisms.

Talmapimod hydrochloride is a selective inhibitor of p38α MAPK, exhibiting an IC50 of 9 nM. This compound effectively suppresses the secretion of pro-inflammatory cytokines, including TNFα, IL-1β, IL-6, and VEGF, while also inhibiting angiogenesis and osteoclast activation. Talmapimod hydrochloride demonstrates efficacy in inhibiting the growth of multiple myeloma cells and promoting apoptosis, making it a valuable tool for investigating various hematological malignancies, such as multiple myeloma and myelodysplastic syndromes.

L-Citronellol ((S)-3,7-Dimethyloct-6-en-1-ol) is an ERK/BACE1/PSEN1 inhibitor known for its anti-allergic and neuroprotective properties. This compound effectively inhibits mast cell activation and subsequent release of inflammatory mediators by targeting the ERK pathway. Additionally, L-Citronellol decreases the activity of BACE1, PSEN1, and acetylcholinesterase (AChE), while reducing TNF-α expression and lipid peroxidation, indicating its potential utility in multi-target approaches for Alzheimer's disease research.