tcsc1038 Rebastinib

Rebastinib (DCC-2036) is a conformational control Bcr-Abl inhibitor for Abl1^WT and Abl1^T315I with IC₅₀ of 0.8 nM and 4 nM, also inhibits SRC, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit.

IC50 & Target: IC50: 0.75±0.11 nM (ABL1^WT), 2±0.3 nM (FLT3), 4±0.3 nM (KDR), 6±0.3 nM (TIE2), 34±6 nM (SRC)^[1]

In Vitro: Rebastinib (DCC-2036) inhibits ABL1^native and the gatekeeper mutant ABL1^T315I with IC₅₀ of 0.8 nM and 4 nM, respectively. Rebastinib potently (IC₅₀ 0.82 nM) inhibits u-ABL1^native, which is thought to exist predominantly in the inactive type II conformation. In addition, Rebastinib also strongly inhibits p-ABL1^native (IC₅₀ 2 nM), which more readily adopts an active, Type I conformation. More significantly, Rebastinib potently inhibits both u-ABL1^T315I (IC₅₀ 5 nM) and p-ABL1^T315I (IC₅₀ 4 nM), both of which exist predominately in the Type I conformation due to stabilization of an activating hydrophobic spine by the T315I mutation. Rebastinib also potently inhibits ABL1H396P (IC₅₀ 1.4 nM), which, like ABL1^T315I, is predisposed to exist predominately in a Type I activated conformation due to the restricted backbone torsional angles imposed by the mutant Pro396. In addition to ABL1, Rebastinib also inhibits the SRC family kinases LYN, SRC, FGR, and HCK, and PDGFRα, and PDGFRβ with IC₅₀ of 29±1, 34±6, 38±1, 40±1, 70±10 and 113±10 nM, respectively. Notably, Rebastinib spared c-KIT (IC₅₀ 481 nM). Rebastinib effectively inhibits the proliferation of Ba/F3 cells expressing native BCR-ABL1^native (IC₅₀ 5.4 nM). Rebastinib also inhibits proliferation of the Ph⁺ cell line K562 (IC₅₀ 5.5 nM). REBASTINIB (DCC-2036) also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC₅₀s ranging from 6-150 nM. Rebastinib effectively inhibits autophosphorylation of BCR-ABL1^native (IC₅₀ 29 nM) and BCR-ABL1^T315I (IC₅₀ 18 nM), as well as the phosphorylation of STAT5 in both cell lines (IC₅₀ 28 nM and 13 nM, respectively)^[1].

In Vivo: A single oral dose of Rebastinib (DCC-2036) at 100 mg/kg afforded circulating plasma levels that exceeded 12 μM for up to 24 hours (data not shown), and effectively inhibited BCR-ABL1 signaling for up to 8 hours in Ba/F3-BCR-ABL1^T315I leukemia cells isolated from BM and spleen of tumor-bearing mice, as assessed by intracellular flow cytometric staining for phospho-STAT5 and immunoblotting of tissue extracts for phospho-BCR-ABL1 and phospho-STAT5. Treatment of mice bearing Ba/F3-BCR-ABL1^T315I leukemia cells with Rebastinib at 100 mg/kg once daily by oral gavage significantly prolonged their survival, while imatinib at 100 mg/kg twice daily is ineffective. In this aggressive allograft model, Rebastinib (DCC-2036) is as effective for treatment of BCR-ABL^T315I leukemia as imatinib at 100 mg/kg twice daily is for treatment of BCR-ABL1^native leukemia, and reduced the leukemia cell burden in the spleens of treated mice^[1].