Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia

Jiang, Kailong; Li, Xuemei; Wang, Chang; Hu, Xiaobei; Wang, Peipei; Tong, Lexian; Tu, Yutong; Chen, Beijing; Jin, Tingting; Wang, Tao; Wang, Hanlin; Han, Yubing; Gui, Renzhao; Yang, Jun; Liu, Tao; Li, Jia; Zhou, Yubo

doi:10.1038/s41375-022-01795-8

Cited by 12 publications

(6 citation statements)

References 50 publications

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“…Especially, almost complete inhibition of p-FLT3, p-STAT5, and p-ERK was observed at the concentration of 20 nM. The feedback activation of CHK1 Ser345 phosphorylation is usually used as a biomarker of CHK1 inhibition Figure B).…”

Section: Resultsmentioning

confidence: 99%

“…In vivo pharmacokinetics study was performed by taking our previous study as a ref . Animal procedures were performed in strict accordance with the Laboratory Animal Management Regulations (State Scientific and Technological Commission Publication No.…”

Section: Methodsmentioning

confidence: 99%

“…The absent/reduced protein level of p53 has been demonstrated in approximately 50% of AML patients, especially for AML with FLT3-ITD mutations, leading to leukemia maintenance and drug resistance upon FLT3i treatment . AML with FLT3-ITD mutation is highly associated with wtp53 dysfunction via different ways such as MDM2/MDM4 overexpression, SIRT1 overexpression, HDAC8 upregulation (resulting p53 deacetylation), PI3K/AKT pathway activation, deubiquitinase YOD1 downregulation (promoting MDM2-mediated p53 degradation), STAT/MAPK pathway activation with BCL2 accumulation (opposing p53 activity), disturbing the nucleocytoplasmic shuttling of p53, dysregulation of NPM (in patients with FLT3-ITD and NPM1 mutant), and aberrant expression of certain miRNAs (e.g., miR-125b). ,− A published data from our group showed dual inhibition of FLT3/CHK1 exhibits a synergetic cytotoxic effect and restoration of the p53 level by CHK1 inhibition can overcome the adaptive resistance to FLT3i …”

Section: Introductionmentioning

confidence: 99%

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Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Wang

et al. 2023

J. Med. Chem.

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FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor 18, which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed high selectivity over c-KIT more than 1700-fold and greatly reduced hERG affinity, with an IC50 value of 58.4 μM. Further mechanistic studies demonstrated 18 can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, 18 demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4–11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Wang

et al. 2023

J. Med. Chem.

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“…All chemical reagents and solvents were purchased from commercial suppliers and used without further purification. + ;found: 276.11, [1,4] oxazine (9) White solid; yield: 46%; 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.37 (d, J = 8.0 Hz, Ar-H, 1H), 7.33 (dd, J = 8.0, 2.5 Hz, Ar-H, 1H), 7.30 (d,J = 2.5 Hz,1H),CH 2 ,2H),CH General procedure B for the synthesis of intermediates (13)(14)(15)(16)(17)(18) Compounds 4 and 5 (1.00 mmol) and TEA (5.00 mmol) were dissolved in DCM (3.0 mL). The corresponding sulfonyl chloride (1.50-2.00 mmol) was added to the solution with an atmosphere of 0 °C and nitrogen.…”

Section: Chemistrymentioning

confidence: 99%

“…17 Our earlier discovery identified that inhibiting FLT3 and CHK1 together is able to restore the p53 pathway activity, which is inactivated by FLT3i, and then overcome FLT3i resistance. 18 Therefore, the concomitant targeting of FLT3 and CHK1 proteins achieves a better AML curative effect probably.…”

Section: Introductionmentioning

confidence: 99%

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

Deng,

Gao,

Wang

et al. 2024

RSC Med. Chem.

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Mechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies

Ou,

Gao,

Habaz

et al. 2024

MedComm

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Tyrosine kinase inhibitor (TKI)‐targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on‐target mechanisms and off‐target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next‐generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual‐targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI‐targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual‐acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI‐targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.

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Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia

Cited by 12 publications

References 50 publications

Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

Mechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies

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