P1/2, N=140, Recruiting, Deciphera Pharmaceuticals LLC | Not yet recruiting --> Recruiting

P1, N=32, Active, not recruiting, AstraZeneca | Completed --> Active, not recruiting | Trial completion date: Aug 2023 --> Aug 2026

P1, N=330, Recruiting, BeiGene | Trial completion date: Aug 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

We identified molecular alterations and immune-related features that distinguish wtRET from mutRET MTC. While RET mutation drives MTC in the absence of other alterations, we showed that wtRET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with oncology immune-oncology agents for selected patients with wtRET MTC.

P1/2, N=170, Recruiting, Treadwell Therapeutics, Inc | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Nov 2024

KTBA decoction manipulates the expression of several key proteins in the p38MAPK/p65NF-κB/AQP4 signaling pathway, modulates gut microbiota and metabolites toward a more favorable profile, improves gut barrier function, delays cardiomyocyte hypertrophy and fibrosis,and improves cardiac function.

They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. This narrative review focused, in the first part, on PGCs' survival/proliferation and differentiation and on the genetic and epigenetic factors involved in the pathogenesis of testicular germ cell tumors (TGCTs) and, in the second part, on the most recent investigations about the KIT-RAS pathway in TGCTs and in other cancers, highlighting the efforts that are being made to identify targetable markers for precision medicine approaches.

In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis.

P1, N=18, Terminated, Pfizer | Trial completion date: Jan 2028 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2026 --> Oct 2023; Study terminated based on internal business considerations and was not based on safety reasons

Furthermore, the binding mode of compound 9f with HPK1 was confirmed by the resolved cocrystal structure. Taken together, this study provides HPK1 inhibitors with a novel scaffold and clear binding mode for further development of HPK1-targeted therapeutic agents.

However, no change in the level of phosphorylated nuclear factor-kB, c-Jun, and p38 transcription factors was observed in GBP1 knockdown cells compared to the control cells. This study concludes that GBP1 may alter the expression of cytokines, chemokines, and effector molecules mediated by MAP kinases and STAT1 transcription factors.

Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

The results also demonstrate MKP-1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin-induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP-1 enhancing compounds as potential novel anti-inflammatory and anti-allergic drugs.

P1/2, N=102, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2 | N=200 --> 102

P1/2, N=140, Not yet recruiting, Deciphera Pharmaceuticals LLC

Furthermore, rutin, quercetin, iso-rhamnetin, and SBF could also inhibit P-p38 and P-JNK expression, thereby suppressing the phosphorylation of the MAPK signaling pathways. Overall, SBF is effective for relieving food allergy and might be a promising anti-allergic therapeutic agent.

P2, N=215, Recruiting, BioMed Valley Discoveries, Inc | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

Besides, it elevated the total apoptosis by 14.68-fold and increased the caspase-3 level by 3.52-fold compared with doxorubicin, which raised it by 4.30-fold, inducing apoptosis by acting as caspase-dependent inducers. These results suggest that 3a is a promising antiproliferative and p38α MAPK inhibitor, confirmed by molecular docking with high compatibility 3a with the p38α MAPK binding site.

These findings provide valuable insights into the molecular pathogenesis of diabetes and highlight the significant role of MKP-5. Moreover, this knowledge holds promise for novel therapeutic strategies targeting MKP-5 for diabetes management.

P1, N=56, Active, not recruiting, Regor Pharmaceuticals Inc. | Recruiting --> Active, not recruiting

P1/2, N=121, Recruiting, 1ST Biotherapeutics, Inc. | Not yet recruiting --> Recruiting

Oxyresveratrol inhibits osteoclast differentiation via MAPK and increases bone density in ovariectomized rats, suggesting it has therapeutic potential for bone diseases such as osteoporosis. We confirmed the osteoporosis prevention effect of OR in Raw 264.7 cells, and future studies should confirm the effect of OR using rat bone marrow-derived cells.

This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.

HMH treatment also upregulated the phosphorylation of JNK, p38, and FOXO3a in SK-Hep1 cells and downregulated the PI3K/AKT signaling pathway. Our findings suggest that HMH may activate the compounds responsible for anticancer effects in hepatocellular carcinoma cells.

P1, N=330, Recruiting, BeiGene

It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF-κB signaling pathway.

The resulting structure-activity relationship (SAR) was rationalized using molecular dynamics simulations against a homology model of MKK3. We expect our findings to expedite the development of novel, potent, selective, and bioactive inhibitors, thus facilitating investigations into MKK3's role in various cancers.

Our findings suggest that while MAPK1 expression, might be a promising biomarker for evaluating oncogenic activity in patients suspected of BCa. We were not able to detect a prognostic/diagnostic role for MAPK1 promoter methylation.

P1, N=32, Completed, AstraZeneca | Active, not recruiting --> Completed

SD rats were divided into control, model, lansoprazole (30mg/kg), SB203580 (2mg/kg), WYI (10.8g/kg, 5.4g/kg and 2.7g/kg) groups. GU was induced using ethanol or indomethacin post-WYI pre-administration...WYI had no significant impact on gastric acid and mucus secretion. WYI demonstrated gastroprotective effects in GU through anti-inflammatory actions and p38 MAPK pathway inhibition, providing insights for innovative GU therapies.

We investigated the growth inhibitory, cisplatin-sensitizing, and pro-apoptotic effects of p38 MAPK inhibition in cisplatin-resistant (SCC-25) and -sensitive (UPCI-SCC090) HNSCC cell lines, using two specific p38 MAPK inhibitors, SB202190 and ralimetinib. In accordance, p-p38 inhibition led to sensitization of pEMT cells to cisplatin-induced cell death; moreover, p-p38 inhibitor treatment cycles significantly decreased the viability of cisplatin-surviving cells. In conclusion, clinically relevant p38 inhibitors might be effective for RCT-resistant pEMT cells in HNSCC patients.

An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4)...Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.

The modified phosphoproteome profile of the homozygous mice in combination with human literature suggests a potential signaling pathway from constitutive TSHR signaling and cAMP activation to the activation of ERK/MAPK signaling. This is the first time that a specific mechanism has been identified for a possible involvement of TSH signaling in thyroid carcinoma development.

In summary, the administration of resveratrol protects motor function and neuronal survival in rats after SCI. Furthermore, resveratrol exerts an anti-inflammatory effect by blocking the JNK/p38MAPK signaling pathway.

P1, N=17, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=240 --> 17

EA treatment enhanced the A2AR activity and inhibited osteoclast formation by inhibition of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1. SCH58261 reversed the effect of EA. These results suggest that EA regulated p38α-MAPK signaling by increasing A2AR activity, which inhibited osteoclastogenesis.

Sorafenib inhibited the proliferation and induced the death of NPC cells in vivo. In conclusion, SLC7A11 plays an important role in the occurrence and progression of NPC and may be a novel target for NPC treatment.

These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.

These results suggest that LaE inhibits the proliferation of human bladder cancer cells. Moreover, the mitogen-activated protein kinase signaling pathway is involved in the inhibition of the proliferation of BFTC-905 cells.

The modified phosphoproteome profile of the homozygous mice in combination with human literature suggests a potential signaling pathway from constitutive TSHR signaling and cAMP activation to the activation of ERK/MAPK signaling. This is the first time that a specific mechanism has been identified for a possible involvement of TSH signaling in thyroid carcinoma development.

Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).