Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)

Lin, Wenye; Hsu, John; Hsieh, Sun-Yuan; Chen, Chiung‐Tong; Song, Jen‐Shin; Yen, Shih-Chieh; Hsu, Tsu; Lu, Chih Heng; Chen, Chun‐Hwa; Chou, Ling-Hui; Yang, Yuanting; Chiu, Ching-Hui; Chen, Ching-Ping; Tseng, Ya-Ju; Yen, Kuei‐Jung; Yeh, Ching-Fang; Chao, Yu‐Sheng; Yeh, Teng‐Kuang; Jiaang, Weir‐Torn

doi:10.1016/j.bmc.2013.03.083

Cited by 14 publications

(9 citation statements)

References 26 publications

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“…A significant decrease in both enzymatic activities (IC 50 > 1000 nM) and cellular potencies (GI 50 > 1000 nM) was observed when the pyridine ring of 14a was moved from the fifth position to the fourth position ( 19 ) of the thiazole ring. According to prior reports, the 2-aminothiazole moiety is conformationally well suited to form hydrogen bond interactions with the kinase hinge region of the ATP pocket, and benzamide is a known scaffold for FLT3 kinase inhibitors . Accordingly, we replaced the pyrimidine group with a benzamide group bearing a solubilizing substituent at the para position of a benzene ring, yielding benzamide 21 .…”

Section: Resultsmentioning

confidence: 99%

“…According to prior reports, the 2-aminothiazole moiety is conformationally well suited to form hydrogen bond interactions with the kinase hinge region of the ATP pocket, 45 and benzamide is a known scaffold for FLT3 kinase inhibitors. 46 Accordingly, we replaced the pyrimidine group with a benzamide group bearing a solubilizing substituent at the para position of a benzene ring, yielding benzamide 21. This approach led to benzamide 21 as only a moderate c-KIT/FLT3 inhibitor with submicromolar activities against GIST-T1 (GI 50 = 647 nM) and MOLM-13 cells (GI 50 = 544 nM).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia

Lin

Yeh

et al. 2019

J. Med. Chem.

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Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia

Lin

Yeh

et al. 2019

J. Med. Chem.

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“…1) [31], [32]. For kinase inhibition specificity screening, BPR1J-340 was tested against 59 protein kinases covering the major oncogenic kinases of human protein kinome.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Antitumor Effects of BPR1J-340, a Potent and Selective FLT3 Inhibitor, Alone or in Combination with an HDAC Inhibitor, Vorinostat, in AML Cancer

et al. 2014

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Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD+ AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD+ AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.

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“…Linifanib competes with ATP in the binding site domain of tyrosine kinase, thus it prevents downstream signaling [64]. Phase II trial studies show that linifanib is useful for the treatment of patients with advanced, refractory colorectal cancer that expresses k-Ras mutations [65]. In an open-label phase II trial linifanib showed interesting clinical activity, as monotherapy, in patients with advanced HCC [66].…”

Section: Linifanibmentioning

confidence: 99%

Diarylureas as Antitumor Agents

et al. 2021

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The diarylurea is a scaffold of great importance in medicinal chemistry as it is present in numerous heterocyclic compounds with antithrombotic, antimalarial, antibacterial, and anti-inflammatory properties. Some diarylureas, serine-threonine kinase or tyrosine kinase inhibitors, were recently reported in literature. The first to come into the market as an anticancer agent was sorafenib, followed by some others. In this review, we survey progress over the past 10 years in the development of new diarylureas as anticancer agents.

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Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)

Cited by 14 publications

References 26 publications

Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia

Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia

Evaluation of the Antitumor Effects of BPR1J-340, a Potent and Selective FLT3 Inhibitor, Alone or in Combination with an HDAC Inhibitor, Vorinostat, in AML Cancer

Diarylureas as Antitumor Agents

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