rebastinib (DCC-2036)

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.

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.

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.

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.

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.

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.

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.

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.

P1/2, N=177, Terminated, Deciphera Pharmaceuticals, LLC | Phase classification: P1b/2 --> P1/2 | Completed --> Terminated; Development program terminated.

P1/2, N=70, Terminated, Deciphera Pharmaceuticals, LLC | N=117 --> 70 | Completed --> Terminated; Development program terminated.

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.

P1/2, N=117, Completed, Deciphera Pharmaceuticals LLC | Active, not recruiting --> Completed | Phase classification: P1b/2 --> P1/2