Evidence map›Paper›PMID 34007045›Full record

ArticleLeukemia2021

Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance.

Ting Song, Yafei Guo, Zuguang Xue, Zongwei Guo, Ziqian Wang, Donghai Lin, Hong Zhang, Hao Pan, Xiaodong Zhang, Fangkui Yin and 3 more

Abstract read
PubMed Publisher
In one paragraph

Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
3.7field-weighted citation impact, top 6% of its field
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

19 citing papers in PubMed, 39 citations in OpenAlex.

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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

13 authors at 3 institutions in 1 country.

Ting Song *State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Yafei Guo *School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
Zuguang Xue *Department of Hematology, Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China.
Zongwei GuoSchool of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
Ziqian WangState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Donghai LinThe Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, China. dhlin@xmu.edu.cn.
Hong ZhangSchool of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
Hao PanState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Xiaodong ZhangState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Fangkui YinState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Hang WangSchool of Innovation and Entrepreneurship, Dalian University of Technology, Dalian, Liaoning, China.
Laura Bonnette UwituzeState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Zhichao ZhangState Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China. zczhang@dlut.edu.cn.ORCID http://orcid.org/0000-0002-2774-2384
Dalian University of Technology · CNDalian Medical University · CNXiamen University · CN

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Herein, we screened a novel inhibitor of the Hsp70-Bim protein-protein interaction (PPI), S1g-2, from a Bcl-2 inhibitor library; this compound specifically disrupted the Hsp70-Bim PPI by direct binding to an unknown site adjacent to that of an allosteric Hsp70 inhibitor MKT-077, showing binding affinity in sub-μM concentration range. S1g-2 exhibited overall 5-10-fold higher apoptosis-inducing activity in CML cells, primary CML blasts, and BCR-ABL-transformed BaF3 cells than other cancer cells, normal lymphocytes, and BaF3 cells, illustrating Hsp70-Bim PPI driven by BCR-ABL protects CML through oncoclient proteins that enriched in three pathways: eIF2 signaling, the regulation of eIF4E and p70S6K signaling, and the mTOR signaling pathways. Moreover, S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines and is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients. By comparing the underlying mechanisms of S1g-2, MKT-077, and an ATP-competitive Hsp70 inhibitor VER-155008, the Hsp70-Bim PPI was identified to be a CML-specific target to protect from TKIs through the above three oncogenic signaling pathways. The in vivo activity against CML and low toxicity endows S1g-2 a first-in-class promising drug candidate for both TKI-sensitive and resistant CML.

Indexed as

Drug Resistance, NeoplasmProtein Interaction Domains and MotifsAnimalsAntineoplastic AgentsApoptosisBcl-2-Like Protein 11Cell ProliferationFusion Proteins, bcr-ablGene Expression Regulation, LeukemicHSP70 Heat-Shock ProteinsHumansImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMaleMiceMice, NudeAntineoplastic AgentsBcl-2-Like Protein 11Fusion Proteins, bcr-ablHSP70 Heat-Shock ProteinsImatinib MesylateProtein Kinase InhibitorsSmall Molecule Libraries

Identifiers

PMID34007045
OpenAlexW3162972687

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.