ravoxertinib (RG7842)

The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

Finally, we discovered that AIBP could control the MAPK signaling pathway-involved genes expression, including P-MEK, MEK, c-Myc, P-ERK1/2, and ERK1/2, and that GDC-0994, a specific ERK1/2 inhibitor, could suppress the AIBP overexpression induced cell migration and proliferation abilities. These findings demonstrated that the ERK/MAPK signaling pathway might be stimulated by AIBP in HCC tissues, leading to increased cell invasion, migration, and proliferation. It was hypothesized that AIBP might act as a useful prognostic and diagnostic marker for HCC.

Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

Notably, several proteins have previously been observed in pancreatic cancer cells with intrinsic resistance to the combined kinase inhibition treatment, suggesting a proteomic signature. We also found that resistant cells are sensitive to small molecule drugs ERK inhibitor GDC-0994, S6K1 inhibitor DG2 and statins.

The ravoxertinib-dependent inhibition of Erk1/2 signaling led to the decrease in erastin efficacy due to the effect on ROS production and the upregulation of ROS scavengers SOD1 and SOD2, resulting in repressed lipid peroxidation. Therefore, it was concluded that the erastin-dependent activation of ferroptosis seems to be a promising approach which can be further developed as an additional strategy for the treatment of HNSCC. As ferroptosis induction via erastin is strongly dependent on the expression of Erk1/2, this MAP kinase can be considered as a predictor for cancer cells' response to erastin.

Next, in vitro characterization and functional analysis of circRNA-0044301 was done by various assays using RNase R, actinomycin D, and RNA fluorescence in situ hybridization, as well as investigations into its use as a drug to treat tumors in a subcutaneous tumorigenesis model...Finally, we investigated the relationship between circRNA-0044301 and ravoxertinib (GDC-0994) and 5-fluorouracil (5-FU) using qRT-PCR, Western blotting, and CCK8 assays...On the mechanism, it acted as a sponge of miRNA-188-5p, could regulate the downstream target DAXX, and modulated the effect of GDC-0994 on ERK1/2 and 5-FU in cells. CircRNA-0044301/miRNA-188-5p/DAXX (ERK1/2) may be a key axis in GC progression, and circRNA-0044301 has immense potential to be a therapeutic target for GC.

Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors.

CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223...Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994...In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro...DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development.

GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single agent activity was observed in two patients with BRAF-mutant CRC.

Here, we tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with the AR inhibitor enzalutamide (ENZ) in androgen-sensitive LNCaP cells and androgen-resistant C4-2 and 22Rv1 cells. Surprisingly, mechanistic studies and Nanostring data suggest that AS602801 likely activates JNK signaling to induce apoptosis. Since AS602801 had sufficient safety and toxicity profile to advance from Phase I to Phase II in clinical trials, repurposing of this compound may represent an opportunity for rapid translation for clinical therapy of CRPC patients.

The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib)...Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors...The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway.