Gomekli (mirdametinib)

P1/2, N=54, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

FDA-approved mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, have shown ~30% tumor shrinkage in 70% and 42% pNF1 patients, respectively. This response was also observed in MPNST cell lines treated with MEK inhibitors. These findings suggest that adaptive activation of upstream and parallel survival pathways may counteract the intended effects of MEK inhibition and support the rationale for combination strategies to improve therapeutic outcomes in NF1-associated tumors.

These studies demonstrate in vitro efficacy for two candidate MPNST therapeutics which could reduce tumor burden and metastasis in NF1 patients.

Mirdametinib represents a meaningful advance in the management of NF1-PNs, offering durable tumor volume reduction, improvements in pain and quality of life, and a manageable safety profile across age groups. While head-to-head comparisons with other MEK inhibitors are lacking, available evidence suggests a favorable balance of efficacy and tolerability that may support its use as a first-line systemic option in appropriately selected patients.

P1, N=8, Not yet recruiting, Springworks Therapeutics Inc.

As a risk factor, RAB7A relating to poor prognosis was identified in our study, and was a potential target for therapeutic agents such as PLX4720 and PD-0325901, while OXSM was the opposite. The 5-DRGs prognostic model can be used to assess the prognosis of patients with CC, and reflect the characteristics of their immune microenvironment. With RAB7A and OXSM as key determinants, this model provides a clinically applicable framework for risk stratification and personalized treatment guidance.

While mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, can reduce tumor volume, surgical resection remains the primary treatment for immediate debulking and symptom relief. These results provide the first evidence that ECM stiffening, such as that arising from postsurgical remodeling, directly drives pNF1 progression and therapeutic resistance. Our findings highlight mechanobiology as a key regulator of tumor behavior and support targeting ECM mechanics to improve clinical outcomes in NF1 patients.

The following ten drugs received FDA approval in 2025 - avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant ROS1 in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant HER2 in NSCLC). This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.

Drug sensitivity screening identified six small molecules (PD0325901, ERK-6604, paclitaxel, ribociclib, TAF1, and lapatinib) that targeted SLC12A5-related pathways. Crucially, multivariate Cox regression analysis confirmed that SLC12A5 was an independent prognostic factor (HR p = 0.04). This study established SLC12A5 as a novel biomarker for GBM, uniquely bridging molecular dysregulation, edema pathogenesis, and radiomics with implications for prognosis and targeted therapy.

In vitro validation narrowed compounds of interest to raltitrexed, alisertib, GTX-007, LY315920, and PD0325901. Treatment with alisertib leads to decrease in H2AK119ub and shift in the immune tumor microenvironment. Alisertib efficacy in HGSC is dependent on functional CBX2 and cell target engagement confirms selectivity for CBX2, supporting that alisertib activity involves CBX2 inhibition.

P1/2, N=50, Recruiting, St. Justine's Hospital | Not yet recruiting --> Recruiting

P1, N=8, Recruiting, University of Minnesota | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027