MAPK

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.

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.

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.

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.

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.

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).

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.

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.

HD202A is a selective dual inhibitor of MNK1 and MNK2, exhibiting IC50 values of 6.09 nM and 8.06 nM, respectively. This compound effectively inhibits the MNK-eIF4E signaling pathway, leading to downregulation of perilipin 2 and SCD1, while upregulating adipose triglyceride lipase and PPARγ coactivator 1α. HD202A enhances mitochondrial fatty acid oxidation, redox homeostasis, and demonstrates significant effects on metabolic health, including suppression of body weight gain, reduction in hepatic lipid accumulation, and improvement in glucose tolerance and insulin sensitivity. These properties make HD202A a valuable tool for researching metabolic dysfunction-associated steatotic liver disease.

MNK1/2-IN-7 is a selective inhibitor of MNK1 and MNK2, primarily targeting the MNK/eIF4E signaling pathway. This compound exhibits potent anticancer activity by effectively inhibiting the phosphorylation of eIF4E, which contributes to reduced cancer cell proliferation. Additionally, MNK1/2-IN-7 demonstrates favorable hERG safety profiles, making it a valuable tool for research applications in oncology, particularly in combination therapies with agents like Ibrutinib.

MEK/PI3K-IN-2 is a potent inhibitor targeting both MEK and PI3K pathways, exhibiting IC50 values of 352 nM for MEK1, 107 nM for PI3Kα, and 137 nM for PI3Kδ. This compound effectively reduces levels of phosphorylated AKT and ERK1/2, demonstrating significant anti-proliferative activity against various tumor cell lines. MEK/PI3K-IN-2 is valuable for research in cancer biology and therapeutic development aimed at disrupting these critical signaling pathways.

SOS1-IN-22 is a selective inhibitor of the son of sevenless homolog 1 (SOS1), crucial for the formation of the KRAS-G12C/SOS1 complex with an IC50 value of 40.28 nM. This compound effectively reduces ERK phosphorylation levels, influencing downstream signaling pathways. SOS1-IN-22 is intended for research applications in cancer biology, particularly relevant to pancreatic carcinoma and appendiceal carcinoma.

MEK/PI3K-IN-1 is a potent inhibitor targeting MEK and PI3K pathways, exhibiting IC50 values of 124 nM for MEK1, 130 nM for PI3Kα, and 236 nM for PI3Kδ. This compound effectively reduces levels of phosphorylated AKT (pAKT) and ERK1/2 (pERK1/2), demonstrating significant anti-proliferative effects in various tumor cell lines. MEK/PI3K-IN-1 serves as a valuable tool for research in cancer therapeutics and signaling pathway analysis.

HPK1-IN-69 is a potent inhibitor of HPK1 with an IC50 of 1.7 nM. This compound disrupts the HPK1-mediated T cell receptor signaling pathway, decreasing SLP76 phosphorylation and enhancing IL-2 release. In vivo studies demonstrate its anti-tumor efficacy in mouse models, making it a valuable reagent for investigating colorectal cancer and MC38 syngeneic tumors.

SOS1-IN-8 is a selective inhibitor of the SOS1 protein, exhibiting IC50 values of 11.6 nM for the SOS1-G12D variant and 40.7 nM for the SOS1-G12V variant. This compound serves as a valuable tool in the study of SOS1-mediated signaling pathways and their implications in various cancers. Its potent inhibitory activity makes it suitable for investigating therapeutic strategies targeting oncogenic mutations associated with SOS1.

SOS1-IN-16 is a selective inhibitor of the SOS1 protein with an IC50 of 7.2 nM, making it a potent tool for studying SOS1-mediated signaling pathways. This compound exhibits inhibitory activity towards CYP3A4 when testosterone is utilized as a substrate, with an IC50 of 8.9 μM. SOS1-IN-16 is primarily applied in cancer research, facilitating the investigation of therapeutic strategies targeting SOS1-related oncogenic processes.

SOS1-IN-7 is a selective inhibitor targeting SOS1, demonstrating potent activity with IC50 values of 20 nM for the SOS1-G12D mutant and 67 nM for the SOS1-G12V variant. This compound effectively disrupts SOS1-mediated signaling pathways, making it a valuable tool for investigating the roles of SOS1 in cancer biology. Its application in research may facilitate the development of therapeutic strategies against tumors driven by mutant RAS signaling.

SOS1-IN-25 is a selective inhibitor of the SOS1 protein, effectively disrupting the formation of the KRASG12C/SOS1 complex with an IC50 of 11.11 nM. This compound demonstrates a dose-dependent reduction in phosphorylated ERK levels, indicating its potential to modulate downstream signaling pathways. SOS1-IN-25 is suitable for research focused on leukemia and other cancers associated with aberrant KRAS signaling.

SOS1-IN-3 is a potent inhibitor of SOS1 (son of sevenless homolog 1) with an IC50 value of 5 nM. This compound exhibits significant anticancer activity, making it a valuable tool for research in cancer biology. Its specificity for SOS1 allows for potential applications in studying the molecular mechanisms of cancer signaling pathways.

SOS1-IN-12 is a highly potent inhibitor of son of sevenless homolog 1 (SOS1), exhibiting a Ki value of 0.11 nM for SOS1 and an IC50 of 47 nM for phosphorylated ERK (pERK). This compound serves as a valuable tool for investigating the role of SOS1 in signaling pathways associated with cancer biology, enabling researchers to explore its potential in anticancer studies and therapeutic applications.

SOS1-IN-10 is a selective inhibitor of SOS1, exhibiting a potent inhibitory effect with an IC50 value of 13 nM specifically targeting the KRAS G12C-SOS1 interaction. This compound is valuable for research studying the role of SOS1 in oncogenic signaling pathways, particularly in cancer models driven by KRAS mutations. Its use can facilitate investigations into therapeutic strategies aimed at modulating RAS-dependent pathways.

HH0043 is a potent SOS1 inhibitor with an IC50 value of 5.8 nM. This orally active compound exhibits significant inhibition of the SOS1 protein, which plays a critical role in Ras signaling pathways. HH0043 is utilized in cancer research to explore therapeutic strategies targeting oncogenic signaling mechanisms.

NSC-658497 is a potent inhibitor of the Ras guanine nucleotide exchange factor SOS1. It competitively binds to SOS1, thereby effectively inhibiting the SOS1-Ras interaction and reducing SOS1's guanine nucleotide exchange factor activity in a dose-dependent manner. This compound has demonstrated significant efficacy in suppressing Ras signaling pathways, ultimately leading to a reduction in associated cell proliferation. NSC-658497 is valuable for research in cancer biology and signaling modulation.

SOS1-IN-4 is a potent inhibitor of SOS1, exhibiting an IC50 of 56 nM for the KRAS-C12C/SOS1 interaction. This compound is instrumental in studies investigating the role of SOS1 in RAS signaling pathways. Its application is significant in cancer research, particularly in models where KRAS mutations contribute to tumorigenesis.

SOS1-IN-2 is a potent inhibitor of SOS1, demonstrating an IC50 value of 5 nM. Its primary mechanism involves the inhibition of SOS1-mediated signaling pathways, making it a valuable tool in cancer research. This compound is suitable for studies focused on tumor biology and the exploration of therapeutic strategies targeting the SOS1 pathway.

SOS1-IN-5 is a potent inhibitor of SOS1, a critical component in RAS signaling pathways. This pyrimidobicyclic derivative disrupts the interaction between RAS and SOS1, effectively blocking KRAS activation and offering broad-spectrum inhibition of KRAS activity. SOS1-IN-5 is intended for use in cancer research, providing valuable insights into therapeutic strategies targeting KRAS-driven malignancies.

SOS1/KRAS-IN-1 is a potent inhibitor targeting the SOS1/KRAS signaling pathway, critical in various cancers. This compound effectively disrupts SOS1-mediated activation of KRAS, providing valuable insights into SOS1/KRAS-mediated diseases. It is suitable for research applications investigating oncogenic signaling and potential therapeutic strategies against KRAS-driven malignancies.

SOF-436 is a selective KRAS inhibitor that targets SOS1-mediated nucleotide exchange, exhibiting an IC50 of 60 μM. Additionally, it effectively disrupts the interaction between KRAS and the effector protein RAF. This compound is primarily utilized in cancer research, providing insights into KRAS-driven oncogenic pathways.

SOS1-IN-9 is a selective inhibitor of SOS1, demonstrating an IC50 of 116.5 nM for the SOS1-KRAS G12C complex. This compound plays a crucial role in inhibiting SOS1-mediated signaling pathways, making it a valuable tool for research into KRAS-driven cancers. Its application extends to studies aimed at elucidating the mechanisms of oncogenic signaling and developing targeted therapeutic strategies.

SOS1-IN-6 is a selective inhibitor of SOS1, demonstrating potent activity with IC50 values of 14.9 nM for the SOS1-G12D variant and 73.3 nM for SOS1-G12V. This compound is primarily utilized in research focused on RAS signaling pathways and cancer biology, offering potential insights into therapeutic strategies targeting oncogenic mutations. Its effectiveness makes SOS1-IN-6 a valuable tool for investigating the modulation of SOS1-related cellular processes.

SAH-SOS1A is a peptide-based inhibitor targeting the SOS1/KRAS protein interaction. It binds with nanomolar affinity (EC50 = 106-175 nM) to both wild-type and various mutant forms of KRAS, including G12D, G12V, G12C, G12S, and Q61H. By directly obstructing nucleotide association, SAH-SOS1A interferes with KRAS-driven cancer cell viability and inhibits the ERK-MAPK phosphosignaling cascade downstream of KRAS, making it a valuable tool for cancer research and therapeutic exploration.

SOS1-IN-13 is a potent inhibitor of son of sevenless homolog 1 (SOS1), exhibiting IC50 values of 6.5 nM for SOS1 and 327 nM for phosphorylated extracellular signal-regulated kinase (pERK). This compound is valuable in anticancer research, providing insights into the role of SOS1 in tumorigenesis and signaling pathways associated with cell proliferation and survival. Its high selectivity allows for targeted studies of SOS1-mediated mechanisms in various cancer models.

KRAS G12C inhibitor 56 is a selective SOS1 inhibitor that exhibits potent inhibitory activity with an IC50 of 1.6 nM. This compound is relevant for cancer research, particularly in studies targeting KRAS-driven malignancies, and may provide insights into therapeutic strategies for tumors harboring KRAS G12C mutations. Researchers can leverage this inhibitor to explore the biochemical mechanisms of cell signaling and proliferation linked to KRAS activation.

ML-3043 is a p38 MAPK inhibitor (IC50 = 0.38 μM). Inhibits the release of IL-1β and TNF-α in a peripheral blood mononuclear cell (PBMC) assay (IC50 values are 0.039 and 0.16 μM respectively).