Rebastinib | Bcl-Abl1 inhibitor

Rebastinib (1020172-07-9) is a potent ABL1 kinase inhibitor (IC₅₀ = 0.8 nM) that binds to amino acid residues that are used to switch between active and inactive conformations.¹ It inhibits both phosphorylated and unphosphorylated ABL1 as well as gatekeeper mutant T315I (IC₅₀ = 4 nM). Rebastinib was active against chronic myeloid leukemia Ba/F3 cells expressing BCR-ABL (IC₅₀ = 19 nM) and BCR-ABLT315I (IC₅₀ = 63 nM) and most kinase mutants.² Rebastinib has been reported to inhibit the growth and metastasis of xenografted MDA-MB-231 triple-negative breast cancer cells by targeting AXL/MET.³ It has also been shown to be a potent inhibitor of Tie2 kinase (IC₅₀ = 0.63 nM).⁴ Rebastinib blocked necroptosis via inhibition of RIPK1 and RIPK3.⁵

References/Citations:

1. Chan et al. (2011), Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036; Cancer Cell 19 556
2. Eide et al. (2011), The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile; Cancer Res. 71 3189
3. Shen et al. (2019), Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET; Int. J. Cancer 144 651
4. Harney et al. (2017), The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors; Mol. Cancer Ther. 16 2486
5. Piao et al. (2023), The Bcr-Abl inhibitor DCC-2036 inhibits necroptosis and ameliorates osteoarthritis by targeting RIPK1 and RIPK3 kinases; Biomed. Pharmacother. 161 114528