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Venetoclax

Other names: RG7601; RO5537382; GDC-0199

Modality: BCL-2 selective inhibitor

Disease State: Acute Myeloid Leukemia Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Summary

Venetoclax is an orally bioavailable small molecule B-cell lymphoma-2 (BCL-2) selective inhibitor designed to restore apoptosis, also known as programmed cell death, by blocking the function of a pro-survival BCL-2 family protein.^1-4 The BCL-2 family proteins, which are expressed at high levels in many tumors, play a central role in regulating apoptosis and, consequently, are thought to impact tumor formation, tumor growth, and resistance.^1,3

Clinical Trials

Venetoclax

NCT ID	Study Phase	Enrollment Status	Study Title
NCT05183035	Phase III	Recruiting	Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)	View details
NCT04895436	Phase II	Recruiting	Study to Assess Change in Disease Activity and Adverse Events of Oral Venetoclax With Intravenous (IV) Obinutuzumab in Adult Participants With Recurring Chronic Lymphocytic Leukemia (CLL)	View details
NCT06524375	Phase II	Active, not recruiting	A Study to Evaluate the Effect of Venetoclax on Participants Receiving a Covalent Bruton's Tyrosine Kinase Inhibitor (cBTKi) for First-line Chronic Lymphocytic Leukemia (1L CLL) to Achieve Deep Durable Remissions to Allow Off-treatment Period	View details

Proposed Mechanism of Action

Venetoclax is a selective, orally bioavailable small molecule inhibitor of BCL-2, an anti-apoptotic protein in the BCL-2 family of proteins.^1,3 Anti-apoptotic BCL-2 proteins prevent cell death by sequestering and preventing the activation of pro-apoptotic proteins.^2,3 Overexpression of anti-apoptotic BCL-2 proteins, observed across a variety of hematologic malignancies, enables cancer cells to evade apoptosis, promoting tumor growth, invasion and resistance to chemotherapy.^1,5-7 Venetoclax is proposed to restore the ability of malignant cells to undergo apoptosis by binding directly to BCL-2, allowing for the displacement of the reserve of previously sequestered pro-apoptotic proteins within the malignant cell to initiate programmed cell death.^1,2

Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208. doi:10.1038/nm.3048
Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007;117(1):112-121. doi:10.1172/JCI28281
Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3(4):279-296. doi:10.1039/c0ib00144a
Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111(7):3322-3330. doi:10.1182/blood-2007-09-078162
Choi J, Choi K, Benveniste EN, et al. Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. Cancer Res. 2005;65(13):5554-5560. doi:10.1158/0008-5472.CAN-04-4570
Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091-3096.
Schmitt CA, Rosenthal CT, Lowe SW. Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med. 2000;6(9):1029-1035. doi:10.1038/79542

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AML
acute myeloid leukemia
BCL-2
B-cell lymphoma-2
CLL
chronic lymphocytic leukemia