MAPK

SOS1-IN-11 is a potent small-molecule inhibitor of SOS1, exhibiting an IC₅₀ value of 30 nM. It is used in research to disrupt the SOS1–KRAS interaction and modulate RAS signaling pathways in cancer models.

MRTX0902 is an orally active and potent SOS1 inhibitor, exhibiting an IC₅₀ of 46 nM (WO2021127429A1; Example 12-10). It is designed to disrupt the SOS1–KRAS interaction, making it a promising candidate for targeting KRAS-driven cancers.

Pyridoxal 5′-phosphate monohydrate is the active coenzyme form of vitamin B6 and is essential for the function of numerous enzymes. It serves as a key cofactor for aromatic L-amino acid decarboxylase, which catalyzes the final step in the biosynthesis of the neurotransmitters dopamine and serotonin. Pyridoxal 5′-phosphate is the primary intracellular phosphorylated form of vitamin B6 and is interconvertible with other forms, including pyridoxine 5′-phosphate (PNP) and pyridoxamine 5′-phosphate (PMP).

Isofraxidin is a coumarin compound derived from *Acanthopanax senticosus* that exhibits anti-invasive and anti-inflammatory properties. It inhibits MMP-7 expression and suppresses cell invasion in human hepatoma cells by reducing ERK1/2 phosphorylation. Isofraxidin also downregulates the expression of iNOS and COX-2 and inhibits the formation of the TLR4/myeloid differentiation protein-2 (MD-2) complex.

Cafestol is an orally active diterpenoid and an inhibitor of ERK2. It exhibits multiple biological activities, including elevation of blood lipids, anti-inflammatory, anti-angiogenic, and anti-diabetic effects. Additionally, cafestol induces apoptosis and autophagy in tumor cells, making it a potential candidate for cancer research.

Lipoteichoic acid is an orally active compound with anti-inflammatory and antitumor properties. It is a key immune molecule found in Gram-positive bacteria that activates the complement system by upregulating C3 and inhibiting CD55. Lipoteichoic acid modulates macrophage autophagy via the PI3K/Akt/mTOR pathway, induces lung injury in mouse models, and inhibits melanin production.

SM-7368 is a potent NF-κB inhibitor that acts downstream of MAPK p38 activation. It suppresses TNF-α-induced upregulation of MMP-9 and is suitable for research on chemotherapeutic strategies targeting TNF-α-mediated tumor invasion and metastasis.

Ganodermanontriol, a sterol isolated from *Ganoderma lucidum*, exerts anti-inflammatory effects in tert-butyl hydroperoxide (t-BHP)-damaged hepatic cells by upregulating heme oxygenase-1 (HO-1) expression. It demonstrates hepatoprotective activity.

FR900359 is a cyclic depsipeptide and a selective inhibitor of Gαq/11/14 proteins in mammals. By targeting Gαq signaling, it effectively inhibits downstream pathways such as the ERK cascade. FR900359 has demonstrated the ability to suppress melanoma cell proliferation, lower blood pressure, and protect against airway hyperreactivity in murine models of allergen sensitization, such as the ovalbumin-induced asthma model.

NDI-101150 is an orally active, potent, and selective inhibitor of hematopoietic progenitor kinase 1 (HPK1). It enhances T cell activation and exhibits antitumor activity by promoting immune-mediated tumor suppression, making it a promising candidate for cancer immunotherapy research.

C16-PAF (PAF (C16)) is a phospholipid mediator and a potent platelet-activating factor that functions as a ligand for the PAF G-protein-coupled receptor (PAFR). It exhibits anti-apoptotic effects by inhibiting caspase-dependent cell death through PAFR activation. C16-PAF is a strong activator of the MAPK and MEK/ERK signaling pathways and is known to induce increased vascular permeability.

Edaxeterkib is a potent inhibitor of extracellular signal-regulated kinase (ERK), designed for cancer research. By targeting the ERK signaling pathway, Edaxeterkib interferes with tumor cell proliferation and survival, making it a valuable tool for studying ERK-driven malignancies.

ABD56 is a bioactive compound that inhibits osteoclast formation and induces osteoclast apoptosis. Its mechanism of action involves suppression of the NFκB and ERK signaling pathways, making it a promising candidate for research in bone metabolism and osteolytic diseases.

Lobeglitazone sulfate is a novel thiazolidinedione and an orally active agonist of peroxisome proliferator-activated receptors (PPARs), with EC50 values of 137.4 nM for PPARγ and 546.3 nM for PPARα. It also acts as an inhibitor of the ERK/JNK/Smad/NF-κB signaling pathways. Lobeglitazone sulfate exhibits anti-inflammatory, anti-diabetic, anti-fibrotic, and anti-atherosclerotic activities, supporting its potential in the treatment of metabolic and inflammatory diseases.

Hydrangenol is an orally active antiphotoaging compound isolated from *Hydrangea serrata* leaves. It prevents wrinkle formation by downregulating matrix metalloproteinases (MMPs) and inflammatory cytokines, while upregulating moisturizing factors and antioxidant gene expression, making it a promising agent for skin health and anti-aging research.

26-Deoxyactein, a bioactive constituent isolated from *Cimicifuga racemosa*, protects against TCDD-induced osteoblast damage. It exerts its effects by inhibiting the upregulation of aryl hydrocarbon receptor (AhR), CYP1A1, and ERK signaling, making it a potential agent for bone health and toxicology research.

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.