rebastinib (DCC-2036) / Ono Pharmaceutical - LARVOL DELTA

Phase Ib clinical and pharmacodynamic study of the TIE2 kinase inhibitor rebastinib with paclitaxel or eribulin in HER2-negative metastatic breast cancer. (PubMed, Clin Cancer Res) - "In patients with MBC, the recommended phase 2 dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg PO BID in combination with paclitaxel or eribulin."

Journal • Metastases • P1 data • PK/PD data • Anorexia • Breast Cancer • Diabetes • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Leukopenia • Musculoskeletal Pain • Neutropenia • Oncology • Pain • Solid Tumor • CTCs • HER-2

Rebastinib inhibits cerebral cavernous malformation in a chronic mouse model. (PubMed, Eur J Pharmacol) - "These findings demonstrate that oral administration of rebastinib effectively suppresses CCM lesion formation and progression and extends survival in a model mouse of CCM, supporting MEKK3 inhibition as a viable therapeutic strategy for CCM disease."

Journal • Preclinical • PDCD10

Tumor-associated macrophage (TAM) score as an independent predictor of recurrence in residual disease after neoadjuvant chemotherapy and for identification of high-risk patients for adjuvant escalation. (ASCO 2026) - "This TAM score predicts recurrence from pre-treatment tissue and identifies macrophage-driven resistance persisting post-NACT, nominating TAM-high residual disease for macrophage-modulating trials. Translational evidence supports this: CSF1R inhibition reduced immunosuppressive TAMs, increased M1-like programs, decreased PD-L1/PD-L2, and enhanced anti-PD-1 efficacy preclinically with ex vivo confirmation. Early-phase data (rebastinib plus chemotherapy in HER2-negative metastatic disease) demonstrate feasibility, supporting prioritization of TAM-high patients with residual disease for trials combining TAM modulation with checkpoint therapy."

Clinical • IO biomarker • Residual disease • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CD163 • CD68 • HER-2 • MRC1 • PD-L1 • PD-L2

Long-Term TIE2 Inhibition in a TEK-Mutated Venous Malformation: A 3-Year Clinical Experience. (PubMed, Biologics) - "Medical treatment options remain limited; while mTOR inhibition with sirolimus has shown moderate benefit, direct TIE2 inhibition has a strong biological rationale and emerging clinical evidence...Compassionate-use treatment with the selective TIE2 inhibitor rebastinib was initiated based on a previously reported patient...Unfortunately, the interruption in the production of the drug made it necessary to try other less specific alternatives like PI3K inhibitor alpelisib. This second long-term clinical experience supports the sustained efficacy and safety of TIE2 inhibition in selected TEK-mutated VMs and highlights the therapeutic gap arised from drug discontinuation, underscoring the need for alternative targeted strategies and prospective evaluation."

Journal • Hematological Disorders • Inflammation • Pain • TEK

Tie2 inhibition disrupts TMEM doorway function and reduces dissemination in pancreatic ductal adenocarcinoma. (PubMed, J Exp Clin Cancer Res) - "Intravasation and dissemination is TMEM doorway mediated in PDAC. TMEM doorway function is mediated by Tie2 signaling. Inhibition of Tie2 pharmacologically and genetically decreases TMEM doorway function and PDAC dissemination. Tie2 inhibition may have therapeutic potential combined with chemotherapy or emerging therapies for PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Pharmacological targeting of the mycothiol cysteine ligase MshC in Mycobacterium abscessus. (PubMed, J Biol Chem) - "Additionally, overexpression of mshC in a susceptible M. abscessus strain increased resistance levels to rebastinib, olverembatinib and SB-224289, but not to rifabutin. Systematic assessment of olverembatinib and SB-224289 in combination with 18 additional drugs revealed distinct synergistic and antagonistic interactions. These results emphasize a yet unexploited chemical structure classes against M. abscessus and highlights the potential of targeting the MSH pathway for future translational developments against M. abscessus lung diseases."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Resistance to VEGFR inhibitors converges from molecular diversity in angiosarcoma cells (AACR 2025) - "However, therapeutic antibodies, such as bevacizumab (Avastin), and chemical inhibitors targeting VEGF pathways have shown limited clinical benefits in angiosarcomas...Then, we examined cellular response to VEGFR2 (Regorafenib, Sorafenib) and Tie2 inhibitors (Rebastinib, Pexmetinib) using cell growth inhibition assays...Furthermore, our results suggest angiosarcoma cells establish a functional convergence that potentiates the signaling activation of VEGF and Tie2 pathways, despite their molecular divergence. Our ongoing work aims to explore the molecular mechanisms promoting resistance to VEGF and Tie2 inhibitors."

Angiosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD31 • PECAM1

TMEM Doorway Mediated Metastasis in Pancreatic Ductal Adenocarcinoma by Tie2 Signaling. (PubMed, bioRxiv) - "Selective pharmacologic inhibition of Tie2 with rebastinib decreases TMEM-associated transient vascular openings, suppresses circulating and hepatic disseminated tumor cells, and-when combined with perioperative FOLFIRINOX after curative-intent resection-improves median survival in murine PDAC. These findings establish TMEM doorways as a common, druggable mechanism of intravasation across epithelial cancers and identify Tie2⁺ macrophages as a therapeutic target to prevent metastatic seeding in PDAC, a disease with no anti-metastatic therapies. TMEM doorway-mediated intravasation in PDAC supports its role as a common gateway for hematogenous metastasis in carcinoma."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Targeting tie-2 receptor with rebastinib (DCC-2036) for angiogenesis Inhibition in early-stage arthritis : enhanced efficacy through liposomal sustained release. (PubMed, Inflammopharmacology) - "Statistical analyses were performed using SPSS software (IBM Corp., Armonk, NY, USA), and significance was assessed using one-way ANOVA. In conclusion, rebastinib encapsulated in pH-dependent liposomes holds promise as a potential therapeutic strategy for the treatment of early arthritis, offering both stability and efficacy in disease suppression."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology

Under ONIOM Layers: Analysis of BCR-ABL Enzyme Inhibitors Through Bond-Critical Points and Natural Orbitals. (PubMed, Molecules) - "This study evaluated Frontier Molecular Orbitals (FMOs) and Bond-Critical Points (BCPs) located in the sites of interactions formed with accessible residues, such as Glu286, Met318, and Asp381. Ponatinib's ONIOM-optimized structure was shown to not only form and preserve prominent interactions, which were shown to be significantly stronger than those formed by rebastinib, but also to be associated with a significant increase in the HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap, indicating its potential to hinder catalytic activity by providing higher chemical stability when compared to rebastinib."

Journal • ABL1 • BCR

DCC-2036 induces repolarization of TAMs to M1-type and enhances CD8+ T cell immunity in TNBC. (PubMed, Mol Ther) - "This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in IL-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036, and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy."

Journal • Oncology • Triple Negative Breast Cancer • CD8 • HCK • HIF1A • IL10

Well-Tempered Metadynamics Simulations Combined with Free Energy Landscape Analysis Uncover the Conformational Transition Pathway of the DYG Motif in LRRK2. (PubMed, ACS Chem Neurosci) - "To investigate the DYG-flipping mechanism, we performed well-tempered metadynamics simulations on LRRK2 in three distinct states: (1) the apo (ligand-free) state, (2) the type I inhibitor-bound state (DNL201), and (3) the type II inhibitor-bound state (rebastinib). These findings elucidate the conformational dynamics of LRRK2 in both unbound and ligand-regulated states as well as the mechanistic details of DYG motif flipping. Our study provides critical structural insights for targeted inhibition of LRRK2 kinase activity."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Rebastinib attenuates acute lung injury by promoting NLRP3 ubiquitination and blocking NLRP3/GSDMD signaling pathway in macrophages and protecting alveolar epithelial cells. (PubMed, Int Immunopharmacol) - "Furthermore, Rebastinib administration alleviated lung inflammatory damage in LPS-induced ALI mouse model. These findings suggest that Rebastinib holds promise as a therapeutic candidate for ALI by inhibiting the activation of pyroptosis and NLRP3 inflammasome on macrophages."

Journal • Acute Lung Injury • Oncology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • CASP1 • IL1B • NLRP3

Discovery of Novel Multiangiogenic Agents Targeting VEGFR2, EphB4, FGFR-1, and TIE-2: Receptor-Based Pharmacophore Modeling, Virtual Screening, and Molecular Modeling Studies. (PubMed, ACS Omega) - "Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins."

Journal • Oncology • EPHB4 • FGFR1 • KDR

Everolimus and Sunitinib potentially work as therapeutic drugs for infantile hemangiomas. (PubMed, Pediatr Res) - "Developed a novel immortalized hemangioma-derived endothelial cell (iHemEC) model that replicates key IH features, overcoming limitations of primary cell models. Identified Sunitinib and Everolimus as promising therapeutic candidates with superior efficacy, supported by transcriptome and protein analyses. Revealed distinct drug mechanisms, with Everolimus targeting PI3K/AKT/mTOR and Sunitinib inducing chromosome instability and DNA damage."

IO biomarker • Journal • Oncology • BCL2 • HIF1A

DCC-2036 inhibits osteosarcoma via targeting HCK and the PI3K/AKT-mTORC1 axis to promote autophagy. (PubMed, World J Surg Oncol) - "Collectively, these findings indicate that DCC-2036 promotes autophagy in osteosarcoma (OS) cells by targeting the HCK/AKT/mTORC1 axis and exerts anti-tumor effects without significant toxicity. Consequently, DCC-2036 emerges as a promising therapeutic agent for the treatment of HCK-overexpressing osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EIF4EBP1 • HCK

Rebastinib inhibits FoxO1 activity and reduces dexamethasone-induced atrophy and its-related gene expression in cultured myotubes. (PubMed, J Physiol Sci) - "Additionally, Rebastinib ameliorated the DEX- and cachexia-induced reduction in contractile force generation. Although the precise mechanisms underlying the action of Rebastinib against muscle atrophy and its efficacy in vivo remains to be elucidated, this compound shows great potential as a therapeutic agent for muscle atrophy."

Journal • Cachexia • Muscular Atrophy • Oncology • Targeted Protein Degradation • FBXO32

The Tie2 antagonist rebastinib reduces ovarian cancer growth in a syngeneic murine model. (PubMed, BMC Cancer) - "Rebastinib plus chemotherapy extends survival in a syngeneic murine model of ovarian cancer. Rebastinib alters proportions of immune cell subsets, increases cytotoxic T cells in ascites, and alters gene expression in tumor cells and macrophages."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor • ANGPT1 • PTPRC

Enhancing immunotherapy efficacy in colorectal cancer: targeting the FGR-AKT-SP1-DKK1 axis with DCC-2036 (Rebastinib). (PubMed, Cell Death Dis) - "Consequently, targeting the FGR-AKT-SP1-DKK1 pathway with DCC-2036 could potentiate immunotherapy by enhancing CD8+ T cell functionality and their tumor infiltration. This strategy may contribute significantly to the refinement of therapeutic approaches for CRC, potentially improving patient prognoses."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • DKK1

DCC-2036-01-003: A Phase 1b/2 Study of Rebastinib (DCC-2036) in Combination With Paclitaxel in Patients With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=177 | Terminated | Sponsor: Deciphera Pharmaceuticals, LLC | Phase classification: P1b/2 ➔ P1/2 | Completed ➔ Terminated; Development program terminated.

Phase classification • Trial termination • Breast Cancer • Endometrial Cancer • Inflammatory Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

A Study of Rebastinib (DCC-2036) in Combination With Carboplatin in Patients With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=70 | Terminated | Sponsor: Deciphera Pharmaceuticals, LLC | N=117 ➔ 70 | Completed ➔ Terminated; Development program terminated.

Enrollment change • Trial termination • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

Phase Ib Clinical and Pharmacodynamic Study of the TIE2 Kinase Inhibitor Rebastinib with Paclitaxel or Eribulin in HER2-Negative Metastatic Breast Cancer (Clin Cancer Res) - P1b | N=28 | NCT02824575 | "This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib orally twice daily in combination with weekly paclitaxel 80 mg/m2 (if ≤2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 and 8 (if ≥1 prior regimen)....No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). Adverse events attributed to rebastinib include muscular weakness and myalgias."

P1 data • Breast Cancer

Group 3 medulloblastomas exploit a transient mechanism of telomere repair mediated by ZSCAN4 which is targetable for therapeutic benefit with brain-penetrant drugs (SNO 2024) - "Rebastinib targeted ZSCAN4, histone acetylation, and telomere repair, was brain penetrant, and significantly enhanced orthotopic-xenograft survival with no toxicity...Pan-cancer whole-genome sequencing data showed that MBs have lower telomeric content than most other cancers. Thus, MBs may be particularly vulnerable to therapeutic strategies that inhibit telomere repair."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

Decoding Inhibitor Egression from Wild-Type and G2019S Mutant LRRK2 Kinase: Insights into Unbinding Mechanisms for Precision Drug Design in Parkinson's Disease. (PubMed, J Phys Chem B) - "Here, two ATP-competitive type I inhibitors, PF-06447475 and MLi-2 (Comp1 and Comp2 ), and one non-ATP-competitive type II inhibitor, rebastinib (Comp3), were considered for this investigation. The binding energy and residence time of the inhibitors followed a similar trend to experimental observations. The findings of this work might provide insight into designing more potent inhibitors for the G2019S LRRK2 kinase."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • CHEK1 • LRRK2

Rebastinib attenuates liver injury following cecal ligation and puncture in male mice. (PubMed, J Med Life) - "In contrast, Rebastinib markedly reduced these levels and mitigated the liver damage. Rebastinib may be a hepatoprotective agent against sepsis-associated liver injury."

Journal • Preclinical • Anesthesia • Hepatology • Infectious Disease • Inflammation • Liver Failure • Septic Shock • CASP1 • ICAM1 • IL6 • KDR • TNFA