ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Abstract
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
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ABT-199 (134) is the first and currently the only approved small-molecule Bcl-2 inhibitor.
“Among them, ABT-199 (134) is the first and currently the only approved small-molecule Bcl-2 inhibitor.361”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [361]
Inhibition of Bcl-2 with ABT199 does not induce thrombocytopenia.
“By contrast, Bcl-2 is dispensable for thrombopoiesis and platelet survival in mice and humans28 and inhibition of Bcl-2 with ABT199 (also known as venetoclax) does not induce thrombocytopenia27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity.
“The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
Bcl-xl inhibition with ABT263 and other small molecular inhibitors induces platelet apoptosis and results in severe thrombocytopenia, which prevents the use of ABT263 and other Bcl-xl specific inhibitors in the clinic even for cancer patients because platelets solely depend on Bcl-xl for survival.
“Bcl-xl inhibition with ABT263 and other small molecular inhibitors induces platelet apoptosis and results in severe thrombocytopenia, which prevents the use of ABT263 and other Bcl-xl specific inhibitors in the clinic—even for cancer patients—because platelets solely depend on Bcl-xl for survival24–27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
ABT263 is highly toxic to both WI38 IR-SCs and platelets.
“As reported, ABT263 was highly toxic to both WI38 IR-SCs (Fig. 1g, middle panel) and platelets16–18,24–27 (Fig. 1g, right panel; Supplementary Fig. 2).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
Cellular senescence plays an important role in hematopoietic aging, including myeloid skewing and expansion of phenotypic hematopoietic stem cells in part to compensate for the decrease in HSC function.
“Cellular senescence also plays an important role in hematopoietic aging, including myeloid skewing (i.e. increase in myeloid cell differentiation and decrease in lymphoid differentiation) and expansion of phenotypic hematopoietic stem cells (HSCs) in part to compensate for the decrease in HSC function27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
Both senescent cells and platelets, but not non-senescent cells, are primarily dependent on Bcl-xl for survival.
“Because both SCs and platelets, but not NCs, are primarily dependent on Bcl-xl for survival16–18,24–27 (Supplementary Fig. 1h), we evaluated the effects of PZ compared with ABT263 on the viability of WI38 NCs (Fig. 1g, left panel), IR-SCs (Fig. 1g, middle panel), and platelets (Fig. 1g, right panel).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
PZ can selectively induce apoptosis in senescent cells, but not platelets, which are dependent on Bcl-xl for survival while having minimal toxicity to non-senescent cells that are less sensitive to Bcl-xl inhibition than senescent cells.
“Therefore, PZ can selectively induce apoptosis in SCs, but not platelets, which are dependent on Bcl-xl for survival while having minimal toxicity to NCs that are less sensitive to Bcl-xl inhibition than SCs16–18,24–27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [27]
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- Authors
- Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., Huang, D. C. S., Hymowitz, S. G., Jin, S., Khaw, S. L., Kovar, P. J., Lam, L. T., Lee, J., Maecker, H. L., Marsh, K. C., Mason, K. D., Mitten, M. J., Nimmer, P. M., Oleksijew, A., Park, C. H., Park, C.-M., Phillips, D. C., Roberts, A. W., Sampath, D., Seymour, J. F., Smith, M. L., Sullivan, G. M., Tahir, S. K., Tse, C., Wendt, M. D., Xiao, Y., Xue, J. C., Zhang, H., Humerickhouse, R. A., Rosenberg, S. H., & Elmore, S. W.
- Affiliations
- AbbVie (United States) (US)
- Genentech (US)
- The University of Melbourne (AU)
- The Royal Melbourne Hospital (AU)
- Corresponding author
- Souers, Andrew J
- ORCID
- Souers, Andrew J
- Leverson, Joel D
- Boghaert, Erwin R
- Catron, Nathaniel D
- Chen, Jun
- Ding, Hong
- Fairbrother, Wayne J
- Huang, David C S
- Hymowitz, Sarah G
- Jin, Sha
- Khaw, Seong Lin
- Kovar, Peter J
- Lam, Lloyd T
- Maecker, Heather L
- Marsh, Kennan C
- Mason, Kylie D
- Nimmer, Paul M
- Park, Cheol-Min
- Phillips, Darren C
- Roberts, Andrew W
- Sampath, Deepak
- Seymour, John F
- Tahir, Stephen K
- Tse, Chris
- Wendt, Michael D
- Zhang, Haichao
- Venue
- Nature Medicine
- Published
- 2013-01-06
- Volume
- 19
- Issue
- 2
- Pages
- 202-208
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2172242534
- Cited by
- 3,058
- References
- 48
- Citations by year
- 2026: 141 · 2025: 207 · 2024: 231 · 2023: 236 · 2022: 222 · 2021: 289 · 2020: 297 · 2019: 255 · 2018: 245 · 2017: 242 · 2016: 241 · 2015: 213 · 2014: 148 · 2013: 85
- FWCI
- 104.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- venetoclax, navitoclax, BCL-2 inhibitor, Bcl-xL, Bcl-2 family proteins, thrombocytopenia, platelet toxicity, apoptosis, chronic lymphocytic leukemia, refractory leukemia, hematologic cancer, oral bioavailability, tumor cell lysis
- MeSH terms
- Aniline Compounds, Animals, Antineoplastic Agents, Blood Platelets, Cell Survival, Dogs, Female, HeLa Cells, Humans, Sulfonamides, Mice, SCID, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Hematologic Neoplasms, Xenograft Model Antitumor Assays, Tumor Burden, bcl-X Protein, Mice
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