The progress of small-molecules and degraders against BCR-ABL for the treatment of CML

Pan, Yani; Zeng, Shenxin; Hao, Rongrong; Liang, Meihao; Shen, Zhengrong; Huang, Wenhai

doi:10.1016/j.ejmech.2022.114442

Cited by 14 publications

(7 citation statements)

References 102 publications

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“…, Arg, Leu) and Dasa appears to be shorter and much easier to find than the linker for CRBN ligand and Dasa ( 23 ), it is tempting to speculate that the association between the UBR E3 Ub ligase and its ligand (amino acids like Arg, Leu, and Lys) may be more flexible and conducive for the PROTAC application. It is worth to note that our single amino acid–based PROTACs exhibit a lower DC 50 (<1 nM) and IC 50 (<0.5 nM) values compared with many previously reported BCR–ABL–targeting PROTACs with DC 50 at the range of 8.5 nM to 30 μM and IC 50 from 3.4 nM to 3.4 μM ( 26 , 35 , 36 ).…”

Section: Discussionmentioning

confidence: 47%

Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

Zhang

et al. 2023

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 47%

Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

Zhang

et al. 2023

Journal of Biological Chemistry

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“…[10] PROTACs, which mediate the recognition of E3 ubiquitin ligase and protein of interest (POI), thereby blocking the protein function by completely degrading POI via the ubiquitin-proteasome system (UPS), have many advantages over kinase inhibitors, such as independent on binding affinity, high catalytic performance, low toxicity. [11] PROTACs designed for the degradation of oncogenic BCR-ABL have been reported (The representative structures are shown in Figure 1), [12][13][14][15] this approach appears to be another effective way to tackle CML.…”

Section: Introductionmentioning

confidence: 99%

Proteolysis Targeting Chimeras (PROTACs) Based on Imatinib Induced Degradation of BCR‐ABL in K562 Cells

Zhang

Chang

et al. 2023

ChemistrySelect

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The proteolysis targeting chimera (PROTAC) technology is widely explored in cancer research and utilized in the treatment of various tumors and malignancies. In the design and optimization of PROTAC, linker is not only critical to the degradation activity of PROTACs, but also greatly affects the membrane permeability, metabolic stability and drug availability. In this study, fifteen new PROTACs based on Imatinib were designed, synthesized, and assessed for their anticancer activity against K562 cells. The CCK‐8 assay results showed that a new PROTAC with a 2‐oxoethyl linker (PROTAC 1) exhibited significant antiproliferative activity against K562 (IC50=0.62±0.02 μM) cells. Western blot analysis showed that PROTAC 1 regulated the protein levels of BCR‐ABL in a dose‐dependent manner and induced degradation of BCR‐ABL in a ubiquitin‐proteasome‐dependent manner in K562 cells. This study provides further evidence for the importance of linker selection in PROTAC design.

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“…To date, several BCR-ABL1 TKIs have been developed and approved for the treatment of CML [3]. Among them, Imatinib is the rst-generation BCR-ABL1 TKI; dasatinib, nilotinib, and bosutinib are the second-generation BCR-ABL1 TKIs; ponatinib is the third-generation BCR-ABL1 TKI [3,4]. These TKIs bind to BCR-ABL tyrosine kinase in an inactive form to inhibit the activity of BCR-ABL tyrosine kinase, thus leading to tumor cells death.…”

Section: Introductionmentioning

confidence: 99%

Pharmacovigilance study of BCR-ABL1 tyrosine kinase inhibitors: A safety analysis of the FDA Adverse Event Reporting System

Zhao

Long

Wang

2023

Preprint

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Background With the increased use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in cancer patients, adverse events (AEs) have garnered considerable interest. We conducted this pharmacovigilance study by using the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluated the AEs of BCR-ABL1 TKIs in cancer patients. Methods We used OpenVigil 2.1 to query AE reports from the FAERS database. Descriptive analysis was used to describe the characteristics of TKIs-associated AE reports. Disproportionality analysis was used to detect safety signals by calculating proportional reporting ratio (PRR) and reporting odds ratios (ROR). Results A total of 85989 AE reports were retrieved from the FAERS database and 3080 significant AE signals were identified. The numbers of significant AE signals for imatinib, nilotinib, dasatinib, bosutinib, and ponatinib were 1058, 813, 232, 186, and 791 respectively. The significant signals were divided into 26 system organ classes (SOCs). The AE signals of imatinib and ponatinib were mainly fixed on general disorders and administration site conditions, while the AE signals of nilotinib, dasatinib, and bosutinib were mainly fixed on investigations, respiratory, thoracic and mediastinal disorders, and gastrointestinal disorders, respectively. Of note, 245, 278, 47, 55, 253 unexpected signals were observed in imatinib, nilotinib, dasatinib, bosutinib and ponatinib, respectively. Conclusions The results of the present study are compatible with clinical experience. The study showed that AE signals were differ among the five BCR‐ABL1 TKIs. Moreover, several unexpected signals were observed in each BCR‐ABL1 TKI. These findings provide valuable information for clinicians to reduce the risk of adverse drug reactions during the BCR‐ABL1 TKIs treatment.

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The progress of small-molecules and degraders against BCR-ABL for the treatment of CML

Cited by 14 publications

References 102 publications

Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

Proteolysis Targeting Chimeras (PROTACs) Based on Imatinib Induced Degradation of BCR‐ABL in K562 Cells

Pharmacovigilance study of BCR-ABL1 tyrosine kinase inhibitors: A safety analysis of the FDA Adverse Event Reporting System

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