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

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

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

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

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

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. (PubMed, Cell Discov) - "Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design."

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

A Study of Rebastinib (DCC-2036) in Combination With Carboplatin in Patients With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=117 | Completed | Sponsor: Deciphera Pharmaceuticals LLC | Active, not recruiting ➔ Completed | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Trial completion • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

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) - P1b/2 | N=177 | Completed | Sponsor: Deciphera Pharmaceuticals LLC | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Breast Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor

TMEM DOORWAYS ARE AN ACTIONABLE TARGET IN PANCREATIC ADENOCARCINOMA (APCM 2023) - "TMEM doorways appear to be a common mechanism of dissemination in PDAC and BC. TMEM doorway concentration is significantly associated with PDAC tumor grade and decreases with neoadjuvant therapy. Inhibition of Tie2 with the selective inhibitor, rebastinib, preclinically leads to decreased TMEM doorway function and dissemination in PDAC."

Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD31 • CD68 • CTCs • PECAM1

The Suppressive Effect of Rebastinib on Triple-negative Breast Cancer Tumors Involves Multiple Mechanisms of Action. (PubMed, Anticancer Res) - "Our studies confirmed rebastinib to be a promising drug candidate for breast cancer treatment with high oral bioavailability and reasonable safety. Our data suggest that the mechanism of action of rebastinib is not limited to CDK16 inhibition but also involves other pathways. This does not diminish the importance of rebastinib as a drug candidate, but reveals the presence of several mechanisms, suggesting a wider scope of possible applications."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

TMEM DOORWAYS ARE AN ACTIONABLE TARGET IN PANCREATIC ADENOCARCINOMA (DDW 2023) - "TMEM doorways appear to be a common mechanism of dissemination in PDAC and BC. TMEM doorway concentration is significantly associated with PDAC tumor grade and decreases with neoadjuvant therapy. Inhibition of Tie2 with the selective inhibitor, rebastinib, preclinically leads to decreased TMEM doorway function and dissemination in PDAC."

Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD31 • CD68 • CTCs • PECAM1

TMEM DOORWAYS ARE AN ACTIONABLE TARGET IN PANCREATIC ADENOCARCINOMA (SSAT 2023) - "TMEM doorways appear to be a common mechanism of dissemination in PDAC and BC. TMEM doorway concentration is significantly associated with PDAC tumor grade and decreases with neoadjuvant therapy. Inhibition of Tie2 with the selective inhibitor, rebastinib, preclinically leads to decreased TMEM doorway function and dissemination in PDAC."

Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD31 • CD68 • CTCs • PECAM1

Activity of a TIE2 inhibitor (rebastinib) in a patient with a life-threatening cervicofacial venous malformation. (PubMed, Pediatr Blood Cancer) - "The patient had facial deformity, daily episodes of pain and inflammation needing massive amount of medication, and difficulty in speech and swallowing, so rebastinib (a TIE2 kinase inhibitor) was approved for compassionate use. After 6 months of treatment, venous malformation had decreased in size and lightened, as well as improved quality-of-life scores."

Journal • Inflammation • Pain

The application of CDK16 inhibitors in the treatment of triple-negative breast cancer (AACR 2023) - "Knockdown of CDK16 could significantly suppress tumor growth and metastasis. Furthermore, in our studies, rebastinib acting as a CDK16 inhibitor displayed its strong suppression of TNBC tumor growth in a dose-dependent manner, indicating rebastinib or its analogs could be druggable and likely used to treat TNBC patients."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

TMEM doorways are an actionable target in pancreatic adenocarcinoma (AACR 2023) - "TMEM doorways appear to be a common mechanism of dissemination in PDAC and breast cancer. TMEM doorway concentration is significantly associated with PDAC tumor grade. Inhibition of Tie2 with the selective inhibitor, rebastinib, preclinically leads to decreased TMEM doorway function and dissemination in PDAC."

Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD31 • CD68 • CTCs • PECAM1

Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors. (PubMed, ACS Chem Biol) - "We find that the binding of MLi-2 (a type I kinase inhibitor) stabilizes a closed kinase conformation and reduces the global dynamics of LRRK2, leading to a more compact LRRK2 structure. In contrast, the binding of Rebastinib (a type II kinase inhibitor) stabilizes an open kinase conformation, which promotes a more extended LRRK2 structure. By probing the distinct effects of the type I and type II inhibitors, key interdomain interactions are found to regulate the communication between the kinase domain and the GTPase domain. The intermediate states revealed in our simulations facilitate the efforts toward in silico design of allosteric modulators that control LRRK2 conformations and potentially mediate the oligomeric states of LRRK2 and its interactions with other proteins."

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