^
    1d
    SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy. (PubMed, J Med Chem)
    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.
    Journal
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS mutation
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    buparlisib (AN2025) • ulixertinib (BVD-523)
    2d
    A Phase 1/2 Study of D3S-002 as Monotherapy or Combination Therapy in Adult Subjects With Advanced Solid Tumors With MAPK Pathway Mutations (clinicaltrials.gov)
    P1/2, N=67, Recruiting, D3 Bio (Wuxi) Co., Ltd | Active, not recruiting --> Recruiting | Trial completion date: Apr 2028 --> Aug 2028 | Trial primary completion date: Apr 2028 --> Aug 2028
    Enrollment open • Trial completion date • Trial primary completion date • First-in-human
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    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
    |
    BRAF V600E • EGFR mutation • KRAS G12C • BRAF V600 • EGFR L858R • EGFR T790M • KRAS G12D • ALK rearrangement • MET exon 14 mutation • EGFR L861Q • ROS1 fusion • EGFR G719X • MET mutation • EGFR S768I • RET rearrangement • KRAS G12 • KRAS G12S • KRAS Q61
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    D3S-002 • elisrasib (D3S-001)
    21d
    CLIN-01194-450: A Study to Assess IPN01194 When Administered Alone in Adults With Advanced Solid Tumours (clinicaltrials.gov)
    P1/2, N=36, Active, not recruiting, Ipsen | Recruiting --> Active, not recruiting | N=220 --> 36
    Enrollment closed • Enrollment change • First-in-human
    1m
    The SHERPA trial: A phase I study combining SHP2 inhibitor RMC-4630 and ERK inhibitor LY3214996 in patients with KRAS-mutant pancreatic, non-small cell lung and colorectal cancer. (PubMed, Eur J Cancer)
    Sufficient exposure to RMC-4630 and LY3214996 was not reached due to the toxicity profile of the combination. Tumor response was not demonstrated at the explored dose levels. Therefore, the dose escalation was discontinued, and the RP2D was not determined.
    P1 data • Journal
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS mutation
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    vociprotafib (RMC-4630) • temuterkib (LY3214996)
    2ms
    Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov)
    P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027
    Trial completion date
    |
    ulixertinib (BVD-523)
    3ms
    HERKULES-3: A Study of ERAS-007 in Patients With Advanced Gastrointestinal Malignancies (clinicaltrials.gov)
    P1/2, N=101, Completed, Erasca, Inc. | Active, not recruiting --> Completed
    Trial completion
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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    BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600
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    Erbitux (cetuximab) • Ibrance (palbociclib) • Braftovi (encorafenib) • ERAS-007
    3ms
    ERK1/2-targeted Cancer therapies: Recent advances, potential drug resistance, and applicability analysis of emerging technologies. (PubMed, Bioorg Chem)
    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.
    Review • Journal
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    MAPK1 (Mitogen-activated protein kinase 1)
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    ulixertinib (BVD-523)
    3ms
    LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients (clinicaltrials.gov)
    P1, N=42, Completed, Nader Sanai | Active, not recruiting --> Completed | Trial completion date: Feb 2028 --> Sep 2025
    Trial completion • Trial completion date
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    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDK4 (Cyclin-dependent kinase 4) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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    Verzenio (abemaciclib) • temuterkib (LY3214996)
    3ms
    A Study to Evaluate Safety, PK and Efficacy of GH55 in Combination With GH21 in Patients With Solid Tumors (clinicaltrials.gov)
    P1/2, N=152, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.
    New P1/2 trial
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    HBI-2376
    4ms
    A Phase II Study of BVD-523 in Metastatic Uveal Melanoma (clinicaltrials.gov)
    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.
    Trial termination
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    DUSP6 (Dual specificity phosphatase 6)
    |
    ulixertinib (BVD-523)
    4ms
    Discovery of Novel and Potent Dual PARP1/ERK Inhibitors as a Promising Strategy for Cancer Therapy. (PubMed, J Med Chem)
    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.
    Journal • BRCA Biomarker • PARP Biomarker
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    BRCA (Breast cancer early onset)
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    BRCA wild-type • BRCA mutation
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    Lynparza (olaparib) • ulixertinib (BVD-523)
    4ms
    Window-of-Opportunity Trial of Ulixertinib for MAPK-Activated Gliomas (clinicaltrials.gov)
    P1, N=40, Recruiting, M.D. Anderson Cancer Center | N=20 --> 40
    Enrollment change
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    FGFR (Fibroblast Growth Factor Receptor) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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    ulixertinib (BVD-523)