ABT-199 (Venetoclax)

Biological Activity

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.

Product Citations

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  J Cell Mol Med. 2022 May;26(9):2646-2657.

  Venetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia
  ABT-199 (Venetoclax) purchased from AbMole

• 

  2020 Dec.

  Zelluläre Seneszenz induziert durch neue zielgerichtete Therapien
  ABT-199 (Venetoclax) purchased from AbMole

• 

  Cell Death and Disease. 2018 Jan 26;9:137-52.

  Downregulation of MCL-1 and upregulation of PUMA using mTOR inhibitors enhance antitumor efficacy of BH3 mimetics in triple-negative breast cancer
  ABT-199 (Venetoclax) purchased from AbMole

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  Oncotarget. 2016 Jan 26;7(4):4195-209.

  Epigenetic modification of TLR4 promotes activation of NFκB by regulating methylCpGbinding domain protein 2 and Sp1 in gastric cancer.
  ABT-199 (Venetoclax) purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Cell Death & Disease (2018). Figure 2. ABT199 (Abmole Bioscience)
	Method	Cell viability analysis
	Cell Lines	MDA-MB-231, MDA-MB-157, and MDA-MB-468 cells
	Concentrations	1 μM
	Incubation Time	24 h
	Results	But treatment with Temsirolimus in combination with ABT263 or ABT199 only induced modest cell viability inhibition.

	Source	Oncotarget (2015). Figure 5. ABT 199 (Abmole BioScience)
	Method	Cell viability assay and Western blot
	Cell Lines	SNU668 and SNU638 cells
	Concentrations	1 µM
	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.

Protocol (for reference only)

Cell Experiment
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.
Concentrations	0~3µM
Incubation time	4 h

Animal Experiment
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
Dosages	100 mg/kg
Administration	oral gavage

Chemical Information

Molecular Weight	868.44
Formula	C45H50ClN7O7S
CAS Number	1257044-40-8
Solubility (25°C)	DMSO 80 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.

References

[1] Vandenberg CJ, et al. Blood. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.

[2] Souers AJ, et al. Nat Med. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.