Mechanism of Action Magnifier – 2016 Desk Reference

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Venetoclax (ABT-199): a Selective Inhibitor of B-Cell Lymphoma-2

Proteins in the B-cell lymphoma-2 (BCL-2) family are key regulators of apoptosis, and the BCL-2 gene is frequently overexpressed in leukemias and lymphomas.1,2 The BH3-only proteins of the BCL-2 family (ie, those having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (ie, sequestration of the proapoptotic Bcl-2 family members).3

BH3 Mimetics


One approach to anticancer treatment has been the development of BH3 mimetic agents, small molecules capable of mimicking BH3-only proteins and thus inhibiting prosurvival proteins and inducing apoptosis in cancer cells.2,3 The first-generation BH3 mimetic navitoclax bound not only to BCL-2 but also to BCL-XL (the physiologic function of which is to protect platelets from apoptosis as they age), and has shown clinical efficacy in some BCL-2–dependent hematologic cancers.2,3 However, thrombocytopenia (a deficiency of platelets in the blood), caused by inhibition of BCL-XL, was observed as a dose-limiting side effect with navitoclax.2,3

Venetoclax

Venetoclax, a second-generation BH3 mimetic, is a synthetic derivative of navitoclax that was designed to protect platelets by selectively binding to BCL-2 with high affinity but not to BCL-X.2,3

Venetoclax is a highly potent, orally bioavailable, BCL-2–selective inhibitor designed to block the function of the BCL-2 protein, thereby restoring apoptosis of cancer cells.2,4

Venetoclax mimics BH3-only proteins, the native ligands of Bcl-2 and apoptosis activators, by binding to the hydrophobic groove of Bcl-2 proteins, thereby repressing Bcl-2 activity and restoring apoptotic processes in tumor cells.5 Venetoclax inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets.2

Venetoclax is under investigation in clinical trials for the treatment of patients with various cancer types, including relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, multiple myeloma, and acute myelogenous leukemia.

References

  1. Ackler S, Oleksijew A, Chen J, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3:e00178.
  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;19:202-208.
  3. Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther. 2013;12:1691-1700.
  4. The ASCO Post. Venetoclax gaining ground in two types of leukemia. www.ascopost.com/issues/january-25,-2015/venetoclax-gaining-ground-in-two-types-of-leuke mia.aspx. Accessed October 6, 2015.
  5. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51:219-227.
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Trabectedin: a DNA-Binding Agent That Covalently Interacts with the Minor Groove of the DNA Double Helix

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings.1 Trabectedin binds to the minor groove of DNA and alkylates guanine at the N2 position, bending the helix toward the major groove.2,3 In this manner, it is [ Read More ]

Uncategorized - January 5, 2016

Duvelisib (IPI-145): a Dual Inhibitor of Phosphoinositide 3-Kinase (PI3K)-Delta and -Gamma

In B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma, the malignant B cells rely on a number of internal and external stimuli to survive, such as the activation of the B-cell receptor, cytokine and chemokine signaling, or direct cell-to-cell interactions. Attracted by chemo­kines, including CXCL12 and [ Read More ]