ABT-199 (GDC-0199) is a new selective small molecule inhibitor of BCL-2 that appears to spare platelets while achieving potent antitumor activity. Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor-bearing mice without causing thrombocytopenia. ABT-199 (GDC-0199) is an engineered version of ABT-263 (Navitoclax) but with much better selectivity.
|Cell lines||CLL cells and platelets|
|Preparation method||Apoptosis analysis Peripheral blood mononuclear cells were purified using Histopaque and cultured in RPMI 1640 medium supplemented with 10% fetal calf serum and 2 mmol/l L-glutamine at2*106 cells/ml. Cells were exposed to different concentrations of ABT-737, ABT-263, or ABT-199 for 4 h before analysis of apoptosis by externalisation of phosphatidylserine (PS) and binding of AnnexinV/fluorescein isothiocyanate (FITC). Platelets isolated from healthy volunteers were cultured in Hepes-buffered saline and exposed to different concentrations of ABT-737, ABT-263, or ABT-199 for 4 h before analysis of apoptosis in the CD41-positive population by externalisation of PS and binding of AnnexinV/FITC.|
|Incubation time||4 h|
|Animal models||C57BL/6 mice were injected (i.v.) with 3x106 T1 lymphoma cells|
|Formulation||formulated in 60% phosal 50PG (standardized phosphatidylcholine concentrate with at least 50% PC and propylene glycol|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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 Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Oncotarget (2015). Figure 5. ABT 199 (Abmole BioScience)|
|Method||Cell viability assay and Western blot|
|Cell Lines||SNU668 and SNU638 cells|
|Incubation Time||24 h|
|Results||Combination 5-aza-dC and LPS treatment enhances binding activity of Sp1 and H3K4me3 in gastric cancer cells via activation of TLR4 signaling.|
Oncotarget. 2016 Jan 26;7(4):4195-209.
ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.
Vandenberg CJ, et al. Blood. 2013 Mar 21;121(12):2285-8. PMID: 23341542.
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Souers AJ, et al. Nat Med. 2013 Feb;19(2):202-8. PMID: 23291630.
|Related Bcl-2 Products|
BH3I-1 is a Bcl-XL-BH3 domain interaction inhibitor with Ki of 2.4 μM (by fluorescence polarization ).It is a selective inhibitor of Bcl-2 family proteins.
Obatoclax is an antagonist of Bcl-2 family members containing four Bcl-2 homology domains, including Bcl-2, Bcl-W, Bcl-XL, and Mcl-1 (KD = ~500 nM).
HA14-1 is a Bcl-2 inhibitor that is widely used for studies of apoptosis with IC50 of ~9 μM.
Sabutoclax(BI-97C1) is a pan-Bcl-2 inhibitor, including Bcl-xL, Bcl-2, Mcl-1 and Bfl-1 with IC50 of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM, respectively.
BM-1074 is a potent and efficacious Bcl-2/Bcl-xL inhibitor with Ki of <1 nM, inactive to Mcl-1.
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