Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3

Li, Yingxiu; Ye, Tian-Yu; Xu, Le; Dong, Yuhong; Luo, Yong; Wang, Chu; Han, Yufei; Chen, Ke; Qin, Mingze; Liu, Yajing; Zhao, Yanfang

doi:10.1016/j.ejmech.2019.111590

Cited by 16 publications

(17 citation statements)

References 20 publications

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“…133 In addition to pacritinib, the Yan group reported a series of dual FLT3 and JAK2 inhibitors, and compound Yan-14j (22, Figure 14 right) showed the most balanced inhibitory activities against FLT3 (IC 50 : 30 nM) and JAK2 (IC 50 : 27 nM) among the reported inhibitors. 134 3.3.3. Dual FLT3 and Aurora Inhibitor.…”

Section: Gsk-3β Reducedmentioning

confidence: 99%

“…On the other hand, multitarget inhibitors have exhibited good antitumor effects and have the ability to overcome resistance by simultaneously suppressing multiple hallmark features of tumors . In fact, the advantages of multitarget inhibitors against AML, including their abilities to overcome drug resistance, have been widely reported. ,,,− It should be noted that some multitarget inhibitors discussed below also have inhibitory activities against other targets that are not reported to be related to FLT3 inhibitor resistance (Table ).…”

Section: Resistance To Flt3 Inhibitormentioning

confidence: 99%

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FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

et al. 2021

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Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.

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Section: Gsk-3β Reducedmentioning

confidence: 99%

Section: Resistance To Flt3 Inhibitormentioning

confidence: 99%

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

et al. 2021

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Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

“…Because JAK2/FLT3 dual inhibitors could exert impacts on JAK2/STATs signaling and the phosphorylation of FLT3 kinase, Li et al evaluated the pharmacophores of momelotinib and tandutinib and utilized hybridization strategy to afford varieties of 4-piperazinyl-2-aminopyrimidine derivatives as potent dual inhibitors for JAK2 and FLT3 (Figure 25a). 129 Representative promising compound Zhao-14j was the most pyrimidine-based inhibitor against JAK2 and FLT3 in the screened library, which caused cell cycle G1/S phase arrest and apoptosis dose-dependently in flow cytometry analysis. The binding mode of Zhao-14j in the FLT3 kinase was further elucidated, as shown in Figure 25b, the NH portion of 2aminopyrimidine and the oxygen atom of acetophenone moiety formed hydrogen bonds with Cys695 and Asp829, respectively, and the morpholine group was fully entered the solvent exposed region.…”

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

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Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

et al. 2020

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Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

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Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors

Jaiswal

Gupta

Ayyannan

2022

Archiv der Pharmazie

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Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl) phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC 50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC 50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.

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Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3

Cited by 16 publications

References 20 publications

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors

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