ERK

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.

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.

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.

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.

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.

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.

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.

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.

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.

(+)-Columbianetin targets JNK and ERK signaling pathways while acting as a TGFβ signaling activator. This compound effectively inhibits UVA-induced phosphorylation of JNK and ERK, decreases MMP-1 production, and reverses collagen degradation. In addition, it mitigates UVA-mediated suppression of Smad2/3 phosphorylation and translocation, providing protective effects against UV-induced cellular damage. (+)-Columbianetin is an essential tool for research focused on skin aging and oxidative stress responses in keratinocytes.

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.