DCC-2036

Biological Activity

DCC-2036, known as the lead "switch-control" inhibitor, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1 (T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph (+) leukemia.

Customer Product Validations & Biological Datas

	Source	PLoS One (2013). Figure 1. DCC-2036
	Method	Immunoblotting
	Cell Lines	EOL-1 cells
	Concentrations	6 nM
	Incubation Time	24 h
	Results	DCC-2036 effectively decreased the phosphorylated-PDGFRa in BaF3 cells expressing FIP1L1-PDGFRa T674I mutant in a concentration- and time-dependent manner while the total protein level of PDGFRa was not affected.

Protocol

Cell Experiment
Cell lines	Ba/F3 cells or primary Ph+ leukemia cells
Preparation method	Cell Proliferation Assays Ba/F3 cells (3×103 cells/well) or primary Ph+ leukemia cells (5×104 cells/well) were plated in triplicate in 96-well plates containing test compounds. After 72h, viable cells were quantified by resazurin (O’Brien et al., 2000) or MTT (Roumiantsev et al., 2002) assay as described. Results represent an average of at least three independent experiments.
Concentrations	0.1~10 mM
Incubation time	72 h

Animal Experiment
Animal models	Allograft and retroviral BM transduction/transplantation mouse models of BCR-ABL1-induced leukemia
Formulation	0.5% CMC/1% Tween-80
Dosages	100 mg/kg once daily
Administration	oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
O'Hare et al. Blood. 2011 Nov 10;118(19):5250-4. PMID: 21908430.

The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile.
Eide et al. Cancer Res. 2011 May 1;71(9):3189-95. PMID: 21505103.

Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
Chan et al. Cancer Cell. 2011 Apr 12;19(4):556-68. PMID: 21481795.