Rebastinib  (Synonyms: DCC-2036)

Rebastinib (DCC-2036) is an orally active, non-ATP-competitive Bcr-Abl inhibitor for Abl1^WT and Abl1^T315I with IC₅₀s of 0.8 nM and 4 nM, respectively. Rebastinib also inhibits SRC, KDR, FLT3, and Tie-2, and has low activity to seen towards c-Kit.

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]

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^[1].
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^[1].
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)^[1].
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)^[1].
Rebastinib 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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

A single dose of Rebastinib (DCC-2036; oral; 100 mg/kg) affords circulating plasma levels that exceeds 12 μM for up to 24 hours, and effectively inhibits 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^[1].
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 STI571 at 100 mg/kg twice daily is ineffective^[1].
In this aggressive allograft model, Rebastinib is as effective for treatment of BCR-ABL^T315I leukemia as STI571 at 100 mg/kg twice daily in BCR-ABL1^native leukemia, and reduces the leukemia cell burden in the spleens of treated mice^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

553.59

Solid

C₃₀H₂₈FN₇O₃

1020172-07-9

CC(C)(C)C1=NN(C(NC(NC2=C(F)C=C(OC3=CC(C(NC)=O)=NC=C3)C=C2)=O)=C1)C4=CC=C5C(C=CC=N5)=C4

Room temperature in continental US; may vary elsewhere.

• [1]. Chan WW, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011, 19(4), 556-568.  [Content Brief]