Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy Article Swipe
Jing Deng
,
Aneel Paulus
,
Douglas D. Fang
,
Alak Manna
,
Guangfeng Wang
,
Hengbang Wang
,
Saijie Zhu
,
Jianyong Chen
,
Ping Min
,
Yan Yin
,
Navnita Dutta
,
Nabanita Halder
,
Gina Ciccio
,
John A. Copland
,
James L. Miller
,
Bing Han
,
Longchuan Bai
,
Liu Liu
,
Mi Wang
,
Donna McEachern
,
Sally Przybranowski
,
Chao‐Yie Yang
,
Jeanne A. Stuckey
,
Depei Wu
,
Caixia Li
,
Jeremy Ryan
,
Anthony Letai
,
Sikander Ailawadhi
,
Dajun Yang
,
Shaomeng Wang
,
Asher Chanan‐Khan
,
Yifan Zhai
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6532938
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6532938
Purpose:Development of B-cell lymphoma 2 (BCL-2)–specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein–protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575).Experimental Design:Computational modeling was used to design “lead” compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models.Results:Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo.Conclusions:These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2–selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1158/1078-0432.c.6532938
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4361958993
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4361958993Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1158/1078-0432.c.6532938Digital Object Identifier
- Title
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Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic MalignancyWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
-
2023-04-01Full publication date if available
- Authors
-
Jing Deng, Aneel Paulus, Douglas D. Fang, Alak Manna, Guangfeng Wang, Hengbang Wang, Saijie Zhu, Jianyong Chen, Ping Min, Yan Yin, Navnita Dutta, Nabanita Halder, Gina Ciccio, John A. Copland, James L. Miller, Bing Han, Longchuan Bai, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Chao‐Yie Yang, Jeanne A. Stuckey, Depei Wu, Caixia Li, Jeremy Ryan, Anthony Letai, Sikander Ailawadhi, Dajun Yang, Shaomeng Wang, Asher Chanan‐Khan, Yifan ZhaiList of authors in order
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https://doi.org/10.1158/1078-0432.c.6532938Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
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goldOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.1158/1078-0432.c.6532938Direct OA link when available
- Concepts
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Cancer research, Apoptosis, Bendamustine, Chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, Biology, Leukemia, Chemistry, Pharmacology, Lymphoma, Biochemistry, ImmunologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| display_name | Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy |
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