Whether they originate in a solid tissue like the breast or in the blood like chronic lymphocytic leukemia (CLL), cancer cells are known for their ability to grow uncontrollably.1 To achieve this uncontrollable growth, cancer cells must be able to grow in the absence of signals that would tell them to grow and ignore the signals that would tell them when to stop dividing or die.1
One way that cancer cells can avoid the signals that tell normal cells to undergo programmed cell death is by increasing the amount of a protein called BCL-2.2 A number of lymphomas and leukemias, including CLL, are known to have higher quantities of the BCL-2 protein than is found in normal cells.3 Finding drugs that inhibit BCL-2 is therefore a potentially effective approach to combat these cancers.3
Venetoclax is the first BCL-2 inhibitor to be approved by the US Food and Drug Administration for the treatment of CLL, small lymphocytic lymphoma, and acute myeloid leukemia.3,4 Despite the drug’s impressive efficacy in treating these cancers, a substantial number of patients receiving venetoclax experience a side effect known as thrombocytopenia, or a reduced number of platelets, which are important in helping blood to clot when blood vessels are injured.4,5 The cause of this side effect is that venetoclax not only inhibits the BCL-2 protein that is protecting cancer cells from programmed cell death, but it also (to a lesser degree) targets a protein called BCL-xL that similarly protects platelets.3,6
Recently, investigators reported the discovery of a new BCL-2 inhibitor that potently targets BCL-2 with less likelihood of interacting with BCL-xL than venetoclax.5 Called ZN-d5, this potential new drug has been evaluated in laboratory-grown human cancer cells and human cancers that have been transplanted into laboratory animals.5
In cell-based experiments, ZN-d5 has shown the ability to stop cancer growth in many different types of cancer.5 Notably, ZN-d5 was shown to be >14 times better at distinguishing between BCL-2 and BCL-xL, and was up to 5 times less toxic toward platelets when compared with venetoclax.5 These values suggest that ZN-d5 may be less likely to cause thrombocytopenia in patients, although human studies will be needed to test this hypothesis.5
Looking at animals harboring human non-Hodgkin’s lymphoma or acute myelogenous leukemia, ZN-d5 was effective as a single agent.5 Furthermore, when used in combination with other anticancer medications, ZN-d5 enhanced the efficacy of other standard-of-care agents.5
Together, these data suggest that ZN-d5 may be a promising new BCL-2 inhibitor for treating patients with leukemias and lymphomas. A phase 1 clinical trial (NCT04500587; https://clinicaltrials.gov/ct2/show/NCT04500587) is currently recruiting patients with non-Hodgkin’s lymphoma and acute myelogenous leukemia at 12 sites outside the United States to evaluate the safety and tolerability of ZN-d5 in humans.5,7
References
- National Cancer Institute. What is cancer? Updated May 5, 2021. www.cancer.gov/about-cancer/understanding/what-is-cancer. Accessed September 28, 2021.
- Montero J, Letai A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 2018;25:56-64.
- Kapoor I, Bodo J, Hill BT, et al. Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance. Cell Death Dis. 2020;11:941.
- VENCLEXTA (venetoclax) [prescribing information]. North Chicago, IL; AbbVie Inc; 2020.
- Pinchman JR, Izadi H, Hopkins CD, et al. Discovery of ZN-d5, a potent BCL-2 inhibitor with improved selectivity for BCL-2. Ann Oncol. 2021;32(suppl_5):S583-S620.
- Qi B, Hardwick JM. A Bcl-xL timer sets platelet life span. Cell. 2007;128:1035-1036.
- ClinicalTrials.gov. Phase 1 first in human study of ZN-d5 as a single agent. Updated July 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04500587. Accessed September 28, 2021.