ulixertinib (BVD-523)

This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

New TANs-related biomarkers have been found that effectively forecast the prognosis of patients suffering from PAAD.

Combining SDUY104 with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.

Firstly, although first-generation ATP-competitive inhibitors such as Ulixertinib have shown antitumor activity in early-phase trials, their efficacy varies widely across patient populations and is often accompanied by mechanism-based toxicities (including rash and diarrhea), highlighting a substantial disconnection between preclinical predictions and clinical outcomes...Furthermore, it highlights emerging technological advances, including innovative modalities that address limitations of traditional ATP-competitive inhibitors, such as targeted protein degradation (TPD) approaches. Collectively, this review seeks to outline a clearer roadmap toward realizing the full therapeutic potential of ERK1/2-targeted interventions in cancer treatment.

P2, N=13, Terminated, Dana-Farber Cancer Institute | Active, not recruiting --> Terminated; This was a Simon two stage design trial that terminated after the first stage due to lack of response.

In an HCT116 xenograft model, I-16 (20 mg/kg) elicited significant tumor growth suppression, outperforming Olaparib (50 mg/kg) or BVD-523 (5 mg/kg) monotherapy and achieving efficacy comparable to their combination. These findings suggest that I-16, as the first potent dual PARP1/ERK inhibitor, represents a promising candidate for cancer therapy.

P1, N=40, Recruiting, M.D. Anderson Cancer Center | N=20 --> 40

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Jan 2027

Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes. These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

P1, N=20, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Sep 2025 --> Sep 2027