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Cited by 76Cell death mechanisms and regulationChronic Lymphocytic Leukemia ResearchCancer-related Molecular Pathways

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Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy

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Liu, Jiuyang, Li, Shuran, Wang, Qin, Feng, Yingcai, Xing, Haimei, Yang, Xuefei, Guo, Ying, Guo, Yunhang, Sun, Hanzi, Liu, Xiaoxin, Yang, Shasha, Mei, Zhu, Zhu, Yutong, Cheng, Zhenzhen, Chen, Shuaishuai, Xu, Min, Zhang, Wenjing, Wan, Nanyan, Wang, Jia, Ma, Yanwen, Zhang, Shuo, Luan, Xudong, Xu, Aiying, Li, Lin, Wang, Haitao, Yang, Xiaolong, Hong, Yuan, Xue, Hai, Yuan, Xi, Hu, Nan, Song, Xiaomin, Wang, Zhiwei, Liu, Xuesong, Wang, Lai, Liu, Ye·2024·Blood
DOI 10.1182/blood.2023019706PMC PMC11076911
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Abstract

Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation–induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

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  • Sonrotoclax is a second-generation BCL2 inhibitor under clinical investigation with activity against BCL2 mutations, and superior potency and selectivity compared with venetoclax.

    “Sonrotoclaxis a second-generation BCL2 inhibitor under clinical investigation with activity againstBCL2 mutations, and superior potency and selectivity compared with venetoclax(63).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [63]

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Metadata

Authors
Liu, J., Li, S., Wang, Q., Feng, Y., Xing, H., Yang, X., Guo, Y., Guo, Y., Sun, H., Liu, X., Yang, S., Mei, Z., Zhu, Y., Cheng, Z., Chen, S., Xu, M., Zhang, W., Wan, N., Wang, J., Ma, Y., Zhang, S., Luan, X., Xu, A., Li, L., Wang, H., Yang, X., Hong, Y., Xue, H., Yuan, X., Hu, N., Song, X., Wang, Z., Liu, X., Wang, L., & Liu, Y.
Affiliations
  • BeiGene (China) (CN)
  • 3Department of Discovery Biology, BeiGene (Beijing) Co, Ltd, Beijing, People’s Republic of China
Corresponding author
Liu, Ye
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2024-05-02
Volume
143
Issue
18
Pages
1825-1836
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2023019706
PMC
PMC11076911
OpenAlex
W4390732017
Cited by
76
References
2
Citations by year
2026: 20 · 2025: 39 · 2024: 17
FWCI
10.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Blood (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
BeiGene
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
venetoclax resistance, BCL-2 inhibitor, hematologic malignancies, chronic lymphocytic leukemia, drug resistance, apoptosis
MeSH terms
Animals, Antineoplastic Agents, Humans, Mutation, Sulfonamides, Apoptosis, Drug Resistance, Neoplasm, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Hematologic Neoplasms, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice

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