Cell lines

Ba/F3 cells expressing native or mutant BCRABL1

Preparation method

The solubility of this compound in DMSO is >27.7 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 ℃ for several months.

Reacting condition

2 ~ 150 nM

Applications

In Ba/F3 cells expressing native BCR-ABL1native, DCC-2036 effectively inhibited cell proliferation with an IC50 value of 5.4 nM. DCC-2036 also potently inhibited Ba/F3 cells expressing BCR-ABL1 mutants that were resistant to Imatinib, Dasatinib (T315A) and Nilotinib (L248R, Y253H, E255V and F359C). In addition, DCC-2036 was effective on the gatekeeper mutant BCR-ABL1T315I (IC50 = 13 nM), on which all three FDA-approved TKIs were ineffective.

Animal models

Mice bearing Ba/F3-BCR-ABL1T315I leukemia cells

Dosage form

100 mg/kg; p.o.

Applications

In mice bearing Ba/F3-BCR-ABL1T315I leukemia cells, a single oral dose of DCC-2036 at 100 mg/kg resulted in a plasma concentration over 12 μM for up to 24 hrs, and effectively inhibited BCR-ABL1 signaling for up to 8 hrs. Treating mice bearing Ba/F3-BCR-ABL1 T315I leukemia cells with DCC-2036 at the dose of 100 mg/kg once daily significantly prolonged their survival.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

DCC-2036 is a conformational control inhibitor of ABL1 with IC50 value of 0.8nM [1].

DCC-2036 is synthesized as a dual-anchoring inhibitor that binds both the switch control pocket E282/R386 pair and the Met318 ATP hinge. It shows a IC50 value of 0.8nM. DCC-2036 also exerts potent inhibition of the gatekeeper mutant ABL1T315I with IC50 value of 4nM. DCC-2036 inhibits ABL1 through forcing the kinase domains into inhibitor-bound, inactive Type II conformations. For the purified ABL1, DCC-2036 strongly inhibits unphosphorylated native ABL1, phosphorylated native ABL1, ABL1H396P, unphosphorylated ABL1T315I and phosphorylated ABL1T315I with IC50 values of 0.82nM, 2nM, 1.4nM, 5nM and 4nM, respectively. It is found that DCC-2036 inhibits ABL1 in a non-ATP-competitive manner. In cellular assay, DCC-2036 inhibits the proliferation of Ba/F3 and K562 cells with IC50 values of 5.4nM and 5.5nM, respectively. Moreover, treatment of DCC-2036 can effectively prolong survival in mice bearing Ba/F3-BCR-ABL1T315I leukemia cells. DCC-2036 is also capable to inhibit BCR-ABL1 in primary leukemic cells from patients with Ph+ leukemia [1].

References:
[1] Chan W W, Wise S C, Kaufman M D, 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.