Article ｜ 26 April 2024

WIKIMOLE—Venetoclax

 

By TargetMol

 

 

 

 

Venetoclax, Catalog number T2119, also known as GDC-0199, ABT 199, Venclexta, ABT-199, and ABT199. Venetoclax is a Bcl-2 inhibitor (Ki <0.01 nM) with high potency, selectivity, and oral activity. Venetoclax can induce autophagy and apoptosis.

 

Menchanism of action

Venetoclax is a specific inhibitor targeting B-cell lymphoma-2 (Bcl-2) protein. Bcl-2 is a protein family that inhibits cell apoptosis and plays a crucial regulatory role in the dynamic balance within cells. Under physiological conditions, most anti-apoptotic proteins of the Bcl-2 gene family are typically sequestered as integral membrane proteins of organelle membranes, while pro-apoptotic proteins are distributed in an inactive form in the cytoplasm or cytoskeletal framework. Upon receiving apoptotic signals, pro-apoptotic proteins undergo conformational changes under the action of certain proteases, translocate from the cytoplasm to organelle membranes, especially the outer mitochondrial membrane, and interact with anti-apoptotic proteins on the membrane, regulating the activity of proteases and nucleases, thus bidirectionally regulating cell apoptosis.

Bcl-2 is overexpressed in various leukemias and lymphomas. Venetoclax binds to the Bcl-2 protein, disrupting its interaction with pro-apoptotic proteins, thereby inducing cell apoptosis.

 

 

Applictaion

Venetoclax is primarily used to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). These conditions commonly involve overexpression of Bcl-2, and Venetoclax works by inducing apoptosis in these cancer cells, thereby reducing tumor burden. Venetoclax is also being studied for use in other types of leukemia and lymphoma, such as acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL), but its use in these areas is still in the clinical research stage.

Venetoclax was approved by the U.S. FDA in 2016 as the world's first Bcl-2 inhibitor, initially used to treat relapsed or refractory CLL. Subsequently, Venetoclax has made significant strides in the treatment of leukemia and lymphoma and has been incorporated into many treatment regimens. The drug is typically used in combination with other chemotherapy drugs or immunotherapy to improve efficacy and reduce the risk of cancer recurrence.

Currently, research and clinical applications of Venetoclax are ongoing, especially for its use in more types of hematologic malignancies. As further understanding of its safety and effectiveness is gained, the role of Venetoclax in the treatment of leukemia and lymphoma will continue to be strengthened and confirmed, while research into resistance to Venetoclax also deepens.

Reference

[1] Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 Family in B Cell Lymphoma. Front Oncol. 2019;8:636. Published 2019 Jan 8. doi:10.3389/fonc.2018.00636

[2] Takei H, Coelho-Silva JL, Tavares Leal C, et al. Suppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasms. Cancer Sci. 2022;113(2):597-608. doi:10.1111/cas.15210

[3] Gao P, Zhang W, Fang X, et al. Simultaneous quantification of venetoclax and voriconazole in human plasma by UHPLC-MS/MS and its application in acute myeloid leukemia patients. J Pharm Biomed Anal. 2023;227:115279. doi:10.1016/j.jpba.2023.115279

[4] Valdez BC, Murray D, Yuan B, Nieto Y, Popat U, Andersson BS. ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells. Oncotarget. 2022;13:319-330. Published 2022 Feb 10. doi:10.18632/oncotarget.28193