Evidence map›Paper›PMID 40795245›Full record

ArticleBlood advances2025

Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.

Jingyi Zhang, Zhenwei Zhang, Jinghua Liu, Shenglin Luan, Jiqiang Qu, Zi Wu, Yafei Kuang, Ping Gong, Yu Bao, Yuetong Wang and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Blood advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Jingyi ZhangDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Zhenwei ZhangDepartment of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Jinghua LiuDepartment of Hematology, Northern Theater General Hospital, Shenyang, People's Republic of China.
Shenglin LuanDepartment of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Jiqiang QuDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Zi WuDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Yafei KuangDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Ping GongDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Yu BaoDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Yuetong WangDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Xiaojing YanDepartment of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, China.ORCID 0000-0003-1673-0369
Samuel WaxmanDivision of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Linxiang ZhaoDepartment of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.ORCID 0000-0003-1045-5781
Yongkui JingDepartment of Pharmacology, Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

abstractThe B-cell lymphoma protein 2 (Bcl-2) inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in older patients with acute myeloid leukemia (AML). However, its clinical efficacy is frequently constrained by the emergence of drug resistance, which involves the overexpression or induction of the myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xL) proteins. To address this challenge, we developed a novel strategy to enhance venetoclax activity and overcome resistance by producing NOXA through the conjugation of dihydroartemisinin (DHA) to venetoclax using a chemical synthesis approach. The produced conjugate, A1, retained potent Bcl-2 inhibitory activity and significantly enhanced NOXA production by promoting interactions between the DHA-derived endoperoxide bridge and heme. Mechanistically, A1 effectively overcomes resistance caused by Mcl-1 and Bcl-xL protein through NOXA-mediated Mcl-1 and cyclin D1 protein degradation, respectively. Optimization of the linker design of A1 yielded polyethylene glycol (PEG)-linked conjugates with increased in vivo efficacy. This study introduced a new generation of venetoclax-based compounds with dual functionality, specifically enhanced NOXA production and robust degradation of antiapoptotic and cell cycle-regulating proteins. Furthermore, we uncovered a promising therapeutic strategy to overcome drug resistance in venetoclax-based AML treatments.

Indexed as

Antineoplastic AgentsArtemisininsBridged Bicyclo Compounds, HeterocyclicCyclin D1Drug Resistance, NeoplasmHemeMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2SulfonamidesAnimalsCell Line, TumorHumansLeukemia, Myeloid, AcuteMiceXenograft Model Antitumor AssaysAntineoplastic AgentsArtemisininsartenimolBridged Bicyclo Compounds, HeterocyclicCCND1 protein, humanCyclin D1HemeMCL1 protein, humanMyeloid Cell Leukemia Sequence 1 ProteinPMAIP1 protein, humanProto-Oncogene Proteins c-bcl-2Sulfonamidesvenetoclax

Identifiers

PMID40795245
PMCPMC12607026

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.