Discovery of <i>N</i>-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

Liang, Xiaofei; Wang, Beilei; Chen, Cheng; Wang, Aoli; Hu, Changwei; Zou, Fengming; Yu, Kewei; Liu, Qingwang; Li, Feng; Hu, Zhenquan; Lü, Tingting; Wang, Junjie; Wang, Li; Weisberg, Ellen; Li, Lili; Xia, Ruixiang; Wang, Qianqian; Ren, Tao; Ge, Jian; Liu, Jing

doi:10.1021/acs.jmedchem.8b01594

Cited by 22 publications

(20 citation statements)

References 42 publications

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“…Both compounds 7d and 7b (data in Supplementary material) showed an excellent selectivity profile, having almost no activity on other kinases including FMS and cKit. High selectivity over cKit might be an opportunity to avoid myelosuppression toxicity, which was reported from a dual FLT3/cKit inhibitor [19][20][21][22] . It is a valuable result to secure such a kinase selectivity profile considering the similarities of the same type III receptor tyrosine kinase (FMS, cKit and FLT3).…”

Section: Resultsmentioning

confidence: 99%

Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Moon

Kim

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC 50 ¼ 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC 50 value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.

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Section: Resultsmentioning

confidence: 99%

Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Moon

Kim

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…This case provided a good model for individualized accurate treatment under the direction of drug sensitivity screening. Even though the ex-vivo approach may not always work as expected as the pharmacodynamics of each patient contribute to the drug sensitivity and toxicity, it did help guide the treatment of many disease, such as chronic myeloid leukemia (CML) (30), acute myeloid leukemia (AML) (31,32) and ALL (33).…”

Section: Discussionmentioning

confidence: 99%

Leukemia With TCF3-ZNF384 Rearrangement as a Distinct Subtype of Disease With Distinct Treatments: Perspectives From A Case Report and Literature Review

et al. 2021

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BackgroundZNF384 rearrangements are found in 5-10% of B-cell acute lymphoblastic leukemia (B-ALL) and 48% of B cell/myeloid mixed phenotype acute leukemia (B/M MPAL). ZNF384-rearranged B-ALL is prone to lineage conversion after chemotherapy. TCF3 is the second most common rearrangement partner of ZNF384 in B-ALL (27.5%) and the most common partner in B/M MPAL (53.3%). TCF3-ZNF384 fusion is related to a poor steroid response and a high frequency of relapse. It is mostly reported in children and adolescents but rarely seen in adults.Patients and MethodsHere, we report a rare case of adult common B-ALL with TCF3-ZNF384 fusion in which the patient relapsed after one cycle of consolidation chemotherapy. Relapsed leukemia cells from the bone marrow were cultured for 72 hours ex vivo, and a panel of 156 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was used for sensitivity screening. The literature on TCF3-ZNF384 fusion was reviewed, and reported cases with TCF3-ZNF384 fusion were summarized. Clinical characteristics were compared between B-ALL and MPAL with TCF3-ZNF384 fusion.ResultsThe relapsed lymphoblasts showed moderate sensitivity to both acute myelocytic leukemia (AML) - and acute lymphoblastic leukemia (ALL)-directed combination chemotherapy schemes, as well as to multiple targeted therapeutic drugs. The hyper-CVAD (B) scheme showed synergistic effects with multiple targeted compounds and had the highest sensitivity. The patient chose the hyper-CVAD (B) scheme combined with sorafenib and achieved complete remission (CR), then consolidated with myeloid-directed homoharringtonine+cytarabine+daunorubicin (HAD) scheme and gained molecular CR. By reviewing the literature, we found that both the genomic landscapes and gene expression profiles of ZNF384-rearranged B-ALL and MPAL are similar and that both diseases have lineage plasticity. The gene expression profile in TCF3-ZNF384-positive patients shows enrichment of hematopoietic stem cell features. No significant differences in clinical characteristics were found between TCF3-ZNF384-positive ALL and MPAL.ConclusionTCF3-ZNF384-positive leukemia may be a distinct subtype of leukemia regardless of immunophenotype. Considering the frequent lineage switches and sensitivity to both ALL- and AML-directed schemes, a uniform strategy directed at both lymphoid and myeloid lineages or at hematopoietic stem cells may be better for TCF3-ZNF384-positive leukemia. Small molecule targeted therapies may be promising treatment options and deserve further investigation.

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“… 150 We and others have shown that low-passage patient-derived primary cells established from acute myeloid leukemia patients, chronic myeloid leukemia (CML) patients, gastrointestinal stromal tumor (GIST) patients, and sarcoma patients can be used for screening and identifying novel kinase inhibitors in preclinical studies. 151 , 152 Lee et al tested the therapeutic landscape of 60 molecule-targeted compounds on 462 PDCs across 14 cancer types and identified lineage-specific drug associations, such as gastric cancers and PI3K inhibitors. 153 Brodin et al evaluated the sensitivity of 525 anticancer agents on patient-derived sarcoma cells and found that the drug sensitivity of the patient sarcoma cells in vitro correlated with the response of the patient to the treatment received.…”

Section: Advances In Efficacy Assessment Models and Technologymentioning

confidence: 99%

An overview of kinase downregulators and recent advances in discovery approaches

Wang

et al. 2021

Sig Transduct Target Ther

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Since the clinical approval of imatinib, the discovery of protein kinase downregulators entered a prosperous age. However, challenges still exist in the discovery of kinase downregulator drugs, such as the high failure rate during development, side effects, and drug-resistance problems. With the progress made through multidisciplinary efforts, an increasing number of new approaches have been applied to solve the above problems during the discovery process of kinase downregulators. In terms of in vitro and in vivo drug evaluation, progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessment. Here, we review the advances in drug design strategies, drug property evaluation technologies, and efficacy evaluation models and technologies. Finally, we discuss the challenges and perspectives in the development of kinase downregulator drugs.

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Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

Cited by 22 publications

References 42 publications

Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Leukemia With TCF3-ZNF384 Rearrangement as a Distinct Subtype of Disease With Distinct Treatments: Perspectives From A Case Report and Literature Review

An overview of kinase downregulators and recent advances in discovery approaches

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