MAPK

6-Demethoxytangeretin is a flavonoid compound isolated from *Citrus reticulata* with demonstrated anti-inflammatory and anti-allergic properties. It inhibits IL-6 production and the expression of related genes in human mast cells by modulating the ALK and MAPK signaling pathways. Additionally, 6-Demethoxytangeretin enhances CRE-mediated transcription in hippocampal neurons, indicating potential neuroregulatory effects.

Larixol is an fMLP inhibitor that also suppresses key signaling pathways involved in immune regulation, including Src kinase, ERK1/2, p38, and AKT phosphorylation. It disrupts the interaction between the βγ subunit of the fMLP receptor Gi protein and downstream effectors, thereby inhibiting fMLP-induced respiratory burst. Larixol effectively inhibits fMLP (0.1 μM)-induced superoxide anion production (IC50: 1.98 μM), cathepsin G release (IC50: 2.76 μM), and neutrophil chemotaxis. It mitigates neutrophil hyperactivation and helps reduce inflammation and tissue damage. Additionally, Larixol derivatives have shown inhibitory activity against TRPC6 functional mutants associated with focal segmental glomerulosclerosis (FSGS).

Gardenin A is an orally active synthetic polymethoxyflavone (PMF) analogue with neurotrophic properties, promoting neurite outgrowth and neuronal differentiation. It enhances neuritogenesis through activation of the MAPK/ERK, PKC, and PKA pathways, independent of TrkA and CREB signaling. Additionally, Gardenin A exhibits sedative, anxiolytic, antidepressant, and anticonvulsant effects, making it a promising compound for neurological and neuropsychiatric research.

Hirsutenone is a bioactive diarylheptanoid derived from *Alnus* species, known for its anti-inflammatory, anti-tumor-promoting, and anti-atopic dermatitis properties. It attenuates adipogenesis by directly binding to PI3K and ERK1 in a non-ATP competitive manner. Hirsutenone is a valuable compound for research related to obesity and metabolic disorders.

SHR2415 is a highly potent, selective, and orally active ERK1/2 inhibitor with IC50 values of 2.8 nM for ERK1 and 5.9 nM for ERK2. It demonstrates strong antiproliferative activity in Colo205 cells with an IC50 of 44.6 nM. SHR2415 is a promising compound for cancer research, particularly in targeting the MAPK/ERK signaling pathway.

FQI1 is a selective inhibitor of Late SV40 Factor (LSF), a transcription factor implicated in oncogenesis. It suppresses cell proliferation with IC50 values of 3 μM in NIH/3T3 cells, 0.79 μM in HeLa cells, and 6.3 μM in A549 cells. FQI1 is a valuable tool for cancer research targeting LSF-driven pathways.

PB1 is a potent intracellular disulfide-reducing agent, designed as a borane-protected analogue of TCEP (tris(2-carboxyethyl)phosphine). It offers several advantages, including excellent cell permeability, the ability to establish high intracellular concentration gradients, and chemical stability. PB1 promotes retinal ganglion cell survival following axotomy in vitro at nanomolar to picomolar concentrations, making it a valuable tool for neuroprotective research.

RGT-018 is a potent, orally active SOS1 inhibitor that exhibits anti-tumor activity by blocking KRAS activation. By disrupting the SOS1–KRAS interaction, RGT-018 effectively inhibits cancer cell proliferation, making it a promising candidate for targeting KRAS-driven malignancies.

Tunlametinib is a highly selective, orally active MEK1/2 inhibitor with an IC50 of 1.9 nM against MEK1. It effectively blocks the RAS-RAF-MEK-ERK signaling cascade, inducing cell cycle arrest and apoptosis. Tunlametinib exhibits strong antiproliferative activity against RAS/RAF mutant cancer cells, including BRAF^V600E and KRAS^G12C mutants, and shows synergistic anti-tumor effects when combined with BRAF, KRAS^G12C, or SHP2 inhibitors, as well as Docetaxel. It is a promising agent for the study of targeted therapies in RAS/RAF-driven malignancies such as melanoma, colorectal cancer, and non-small cell lung cancer.

PF-07265028 is a selective inhibitor of hematopoietic progenitor kinase 1 (HPK1/MAP4K1) with potent cellular activity, demonstrated by a pSLP76 IC50 of 17 nM. It is a promising compound for cancer research, particularly in studies involving immune regulation and tumor immunotherapy.

Migoprotafib (GDC-1971; compound 199) is a selective SHP2 inhibitor that suppresses the MAPK/ERK signaling pathway. It exhibits antitumor activity and is under investigation for its potential in targeting SHP2-driven cancers.

HKB99 is an allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that induces apoptosis and suppresses cell migration by inhibiting the formation of invasive pseudopodia. It increases oxidative stress, activates the JNK/c-Jun pathway, and downregulates AKT and ERK signaling. HKB99 is a promising compound for the study of non-small cell lung cancer (NSCLC).

7-Hydroxyflavone is an orally active flavonoid isolated from *Clerodendrum phlomidis*, exhibiting notable anti-inflammatory activity. It protects renal cells from nicotine-induced cytotoxicity through activation of the ERK/Nrf2/HO-1 signaling pathway. Additionally, 7-Hydroxyflavone inhibits PKM2 with an IC50 of 2.12 μM, and suppresses COX-2 and 5-LOX with IC50 values of 27 μg/mL and 33 μg/mL, respectively.

Iruplinalkib (WX-0593) is an orally active and selective ALK/ROS1 inhibitor that effectively blocks tyrosine autophosphorylation of ALK, mutant ALK, and EGFR, with IC50 values ranging from 5.38 to 16.74 nM. Additionally, it inhibits the transport activity of MATE1, MATE2K, P-gp, and BCRP. Iruplinalkib is under investigation for the treatment of non-small cell lung cancer (NSCLC).

α-Amyrin is an orally active pentacyclic triterpenoid that activates the ERK and GSK-3β signaling pathways. It is studied for its potential in treating metabolic syndrome induced by a high-fructose diet and cognitive dysfunction associated with reduced cholinergic neurotransmission.

Gondoic acid (cis-11-Eicosenoic acid) is a monounsaturated long-chain fatty acid found in various plant oils and nuts. It exhibits anti-inflammatory activity by reducing reactive oxygen species (ROS) production and inhibiting the PKCθ/ERK/STAT3 signaling pathway. Gondoic acid is also utilized as a raw material in medical applications and as a moisturizing agent in cosmetic formulations.

Tauroursodeoxycholate (Tauroursodeoxycholic acid; TDUCA) dihydrate is an inhibitor of endoplasmic reticulum (ER) stress that significantly downregulates pro-apoptotic molecules, including caspase-3 and caspase-12. Additionally, it suppresses ERK signaling, contributing to its cytoprotective and anti-apoptotic effects.

MAP855 is a highly potent, selective, ATP-competitive, and orally active MEK1/2 kinase inhibitor, with an IC50 of 3 nM for the MEK1–ERK2 cascade and a pERK EC50 of 5 nM. It exhibits equipotent inhibitory activity against both wild-type and mutant forms of MEK1/2, making it a valuable tool for MAPK pathway research.

Pamoic acid disodium is a potent agonist of GPR35, with an EC50 of 79 nM. It induces GPR35 internalization and activates ERK1/2 signaling with EC50 values of 22 nM and 65 nM, respectively. Additionally, it effectively recruits β-arrestin2 to GPR35 and exhibits antinociceptive properties, supporting its potential in pain research.

AL-8810 is a potent and selective antagonist of the prostaglandin F2α (PGF2α) receptor (FP receptor), with Ki values of 0.2 ± 0.06 μM in mouse 3T3 cells and 0.4 ± 0.1 μM in rat A7r5 cells. In addition to its antagonistic activity, AL-8810 also activates MAPK and ERK1/2 signaling pathways. It is commonly used in research related to elevated intraocular pressure (OHT) and primary open-angle glaucoma (POAG).

JWG-071 is a kinase-selective chemical probe targeting ERK5, with an IC50 of 88 nM. It also exhibits inhibitory activity against LRRK2, with an IC50 of 109 nM, making it a valuable tool for studying ERK5- and LRRK2-related signaling pathways.

Methylnissolin (Astrapterocarpan), a natural compound isolated from *Astragalus membranaceus*, inhibits PDGF-BB-induced vascular smooth muscle cell proliferation with an IC50 of 10 μM. It exerts its effects by suppressing PDGF-BB-induced phosphorylation of ERK1/2, thereby blocking activation of the ERK1/2 MAP kinase signaling cascade.

DMU-212 is an orally active methylated derivative of Resveratrol that exhibits antimitotic, anti-proliferative, antioxidant, and pro-apoptotic activities. It induces mitotic arrest by promoting apoptosis and activating ERK1/2 signaling.

Mogrol, a biometabolite of mogrosides, exerts its biological activity by inhibiting the ERK1/2 and STAT3 signaling pathways, suppressing CREB activation, and activating AMPK signaling.

CGP78850 is a potent and selective inhibitor that disrupts Grb2 SH2-phosphopeptide interactions. It serves as a valuable tool for investigating Grb2-mediated signaling pathways and holds potential for cancer research applications.

JG26 is a potent ADAM inhibitor with IC50 values of 12 nM for ADAM8, 1.9 nM for ADAM17, and 150 nM for ADAM10. It also inhibits MMP-12 with an IC50 of 9.4 nM. JG26 suppresses AngII-induced EGFR transactivation and ERK activation, upregulates ACE2 expression, inhibits CD23 shedding, and reduces SARS-CoV-2 infection. Additionally, JG26 demonstrates anti-metastatic effects in colorectal cancer and holds research potential in Hodgkin lymphoma and vascular diseases.

TMCB (CK2/ERK8-IN-1) is a dual inhibitor of casein kinase 2 (CK2) and ERK8 (MAPK15/ERK7), with a Ki of 0.25 µM for CK2 and IC50 values of 0.50 µM for both targets. It also exhibits binding affinity for PIM1 (Ki = 8.65 µM), HIPK2 (Ki = 15.25 µM), and DYRK1A (Ki = 11.9 µM). CK2/ERK8-IN-1 demonstrates pro-apoptotic activity and is a useful tool for studying kinase-mediated cell survival pathways.

Gambogic amide is a potent and selective TrkA agonist that induces tyrosine phosphorylation of TrkA and activates downstream signaling pathways, including Akt and MAPK. It specifically binds to the cytoplasmic juxtamembrane domain of TrkA, promoting receptor dimerization and activation. Gambogic amide exhibits neuroprotective effects by preventing glutamate-induced neuronal cell death and demonstrates improved efficacy in a transient middle cerebral artery occlusion (MCAO) model of stroke, supporting its potential use in research on neurodegenerative diseases and stroke.

CDPPB is a selective, orally active allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5). It enhances AKT and ERK1/2 signaling and upregulates BDNF mRNA expression. CDPPB also inhibits caspase-3 activation and mitigates mitochondrial dysfunction, demonstrating therapeutic potential in improving cognitive impairment, depression, and Huntington’s disease.

Withanolide B, a bioactive constituent of *Withania somnifera* Dunal, promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) through activation of the ERK1/2 and Wnt/β-catenin signaling pathways. It also demonstrates neuroprotective, anti-arthritic, anti-aging, and anti-cancer properties.

Magnolin, a major bioactive compound from *Magnolia liliiflora*, targets the active sites of ERK1 and ERK2, inhibiting the Ras/ERKs/RSK2 signaling pathway with IC50 values of 87 nM and 16.5 nM, respectively.

RLX-33 is a potent, selective, and blood-brain barrier-permeable antagonist of the relaxin family peptide 3 receptor (RXFP3), with an IC50 of 2.36 μM. It effectively inhibits relaxin-3-induced phosphorylation of ERK1 and ERK2, with IC50 values of 7.82 μM and 13.86 μM, respectively. RLX-33 suppresses RXFP3 agonist (R3/I5)-induced food intake in rats and is a valuable tool for metabolic syndrome research.

HIOC is a potent and selective activator of the TrkB (tropomyosin receptor kinase B) receptor, capable of crossing both the blood-brain and blood-retinal barriers. It activates the TrkB/ERK signaling pathway, reduces neuronal apoptosis, and has been shown to attenuate early brain injury following subarachnoid hemorrhage (SAH). Additionally, HIOC exhibits neuroprotective effects in animal models of light-induced retinal degeneration.

Asperulosidic Acid (ASPA) is a bioactive iridoid glycoside isolated from the herb Hedyotis diffusa Willd., exhibiting anti-tumor, antioxidant, and anti-inflammatory properties. Its anti-inflammatory effects are associated with the downregulation of proinflammatory cytokines such as TNF-α and IL-6, mediated through inhibition of the NF-κB and MAPK signaling pathways.

Sulforaphene, a natural compound isolated from radish seeds, exhibits an ED₅₀ of approximately 2 × 10⁻⁴ M against velvetleaf seedlings. It promotes apoptosis and inhibits migration in cancer cells by suppressing signaling pathways including EGFR, phosphorylated ERK1/2 (p-ERK1/2), and NF-κB.

ASN007 (ERK-IN-3) benzenesulfonate is a potent, orally active ERK1/2 inhibitor with low single-digit nanomolar IC50 values. It is under investigation for the treatment of cancers driven by RAS mutations.

ERK1/2 Inhibitor 7 is a highly potent ERK inhibitor, exhibiting an IC50 of 0.94 nM against ERK2. It is referenced in patent WO2021110168A1 (compound WX006).

EVT801 is an orally active, selective VEGFR-3 inhibitor (IC50=11 nM) with potent antitumor properties. It suppresses VEGF-C-induced human endothelial cell proliferation and tumor-associated lymphatic angiogenesis in mouse models. EVT801 reduces tumor hypoxia, immunosuppressive cytokines (CCL4, CCL5), and myeloid-derived suppressor cell (MDSC) production. When combined with immune checkpoint therapy (ICT), EVT801 enhances response rates and improves tumor inhibition in cancer mouse models. Additionally, EVT801 is a click chemistry reagent containing an alkyne group, enabling copper-catalyzed azide-alkyne cycloaddition (CuAAC) with azide-containing molecules.

I-287 is an orally active and selective protease-activated receptor 2 (PAR2) inhibitor that functions as a negative allosteric modulator, specifically targeting Gαq and Gα12/13 signaling pathways and their downstream effectors. By disrupting PAR2-mediated signaling, I-287 effectively reduces inflammation in preclinical models, including Complete Freund's Adjuvant (CFA)-induced inflammation in mice.

Fenoprofen (LILLY-53858) is a nonsteroidal anti-inflammatory drug (NSAID) that functions primarily by inhibiting cyclooxygenase (COX) enzymes, thereby reducing the synthesis of pro-inflammatory prostaglandins. In addition to its classical NSAID activity, Fenoprofen has been identified as a positive allosteric modulator (PAM) of melanocortin receptors (MCRs), enhancing MCR-mediated signaling. Fenoprofen also promotes ERK1/2 activation in HEK293T cells, suggesting additional modulation of intracellular signaling pathways involved in inflammation and cellular proliferation.

(rel)-AR234960 is a selective and competitive agonist of the MAS G protein-coupled receptor (GPCR), known for its role in cardiovascular regulation. Upon binding to the MAS receptor, (rel)-AR234960 activates the ERK1/2 signaling cascade, leading to the upregulation of connective tissue growth factor (CTGF) and downstream collagen subtype genes, including COL1A1 and COL3A1. This activation promotes collagen synthesis in cardiac fibroblasts via the MAS–ERK1/2–CTGF axis, contributing to extracellular matrix remodeling and the progression of cardiac fibrosis. The fibrotic effects of (rel)-AR234960 can be reversed by the MAS inverse agonist AR244555 or by inhibition of MEK1, a key upstream regulator of ERK1/2.

ACA-28 (compound 2a) is a potent modulator of the ERK MAPK signaling pathway that exerts anticancer effects through a unique mechanism involving ERK hyperactivation. Rather than inhibiting ERK activity directly, ACA-28 induces sustained ERK activation, which paradoxically triggers apoptosis in cancer cells. It demonstrates selective cytotoxicity, inhibiting the growth of melanoma cells (SK-MEL-28) with an IC₅₀ of 5.3 μM, while showing lower toxicity toward normal human melanocytes (NHEM), with an IC₅₀ of 10.1 μM. ACA-28's ability to exploit ERK signaling dysregulation for selective induction of apoptosis makes it a promising candidate for further development in cancer therapy, particularly in ERK-dependent malignancies.

Pyridoxal 5′-phosphate hydrate (PLP) is the biologically active form of vitamin B6 and serves as an essential cofactor for over 100 enzymatic reactions, particularly those involved in amino acid metabolism. It plays a critical role in the function of aromatic L-amino acid decarboxylase, the enzyme responsible for catalyzing the final step in the synthesis of key neurotransmitters such as dopamine and serotonin. PLP is the principal coenzyme form generated through intracellular phosphorylation of vitamin B6 precursors and is interconvertible with other phosphorylated forms, including pyridoxine 5′-phosphate (PNP) and pyridoxamine 5′-phosphate (PMP).

ERK-IN-4 is a selective extracellular signal-regulated kinase (ERK) inhibitor that preferentially binds to ERK2 with a dissociation constant (K_d) of 5 μM. It specifically inhibits the phosphorylation of downstream ERK substrates, including Rsk-1 and Elk-1, without significantly affecting the phosphorylation of ERK itself by its upstream activators MEK1/2. This targeted mode of action allows ERK-IN-4 to modulate ERK signaling output without disrupting upstream pathway dynamics, making it a useful tool for studying ERK-mediated cellular processes and potential therapeutic intervention in ERK-driven diseases.

AT-533 is a potent inhibitor of heat shock protein 90 (Hsp90) and herpes simplex virus (HSV), exhibiting strong antitumor and antiviral activities. It suppresses tumor growth and angiogenesis by disrupting the HIF-1α/VEGF/VEGFR-2 signaling axis, a critical pathway in tumor vascularization and progression. Additionally, AT-533 inhibits key downstream signaling cascades, including Akt/mTOR/p70S6K, ERK1/2, and FAK pathways. In endothelial cells, specifically human umbilical vein endothelial cells (HUVECs), AT-533 effectively inhibits tube formation, cell migration, and invasion, highlighting its anti-angiogenic properties. These combined effects position AT-533 as a promising candidate for cancer therapy and angiogenesis-related disease research.

Keracyanin chloride is an orally active anthocyanin compound with potent antioxidant, anti-inflammatory, and hypoglycemic properties. It exerts its biological effects by inhibiting the NF-κB/FAK/MAPK signaling pathways, which are central to inflammation, cell adhesion, and metabolic regulation.

Cearoin is a bioactive compound that promotes both autophagy and apoptosis by inducing reactive oxygen species (ROS) production and activating the ERK signaling pathway. Through this dual mechanism, cearoin contributes to the regulation of cellular stress responses and programmed cell death. Its ability to modulate these processes makes it a valuable candidate for research in cancer biology and other diseases involving dysregulated autophagy or apoptosis.

(E)-Osmundacetone is a geometric isomer of Osmundacetone, exhibiting notable biological activity. It significantly inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), including JNK, ERK, and p38, which are key mediators of cellular stress and inflammatory responses. Through this inhibition, (E)-Osmundacetone exerts neuroprotective effects, particularly against oxidative stress-induced neuronal damage. These properties make it a promising compound for research in neurodegenerative diseases and oxidative stress-related conditions.

Firazorexton (TAK-994 free base) is an orally active, brain-penetrant, and highly selective agonist of the orexin type 2 receptor (OX2R). By activating OX2R, Firazorexton enhances wakefulness and has demonstrated efficacy in preclinical models, notably improving narcolepsy-like symptoms in mice. Its targeted action on the orexin system positions it as a promising therapeutic candidate for sleep disorders such as narcolepsy and excessive daytime sleepiness.

Penehyclidine hydrochloride (also known as Penequinine hydrochloride) is a selective anticholinergic agent that acts as an antagonist of muscarinic M1 and M3 receptors. It exerts anti-inflammatory effects by modulating immune signaling in lung tissue, notably through activation of the NF-κB pathway and inhibition of pro-inflammatory cytokine release. In preclinical studies, Penehyclidine hydrochloride has been shown to alleviate pulmonary inflammation in rat models of chronic obstructive pulmonary disease (COPD), particularly under conditions of mechanical ventilation. These properties suggest its potential utility in managing respiratory inflammatory conditions and improving outcomes in mechanically ventilated patients with COPD.