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Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment of existing mitophagy inducers limit their further applications. In this study, a platform for AD therapy is developed using nanosized mesenchymal-stem-cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability of MSC-EVs-SHP2 is demonstrated in AD-mice, facilitating SHP2 delivery to the brain. In addition, MSC-EVs-SHP2 significantly induces mitophagy of neuronal cells, which alleviates mitochondrial damage-mediated apoptosis and NLRP3 inflammasome activation. Mitophagy further diminishes neuronal cells apoptosis and neuroinflammation, culminating with rescued synaptic loss and cognitive decline in an AD mouse model. The EV-engineering technology provides a potential platform for effective AD therapy by inducing mitophagy., (© 2022 Wiley-VCH GmbH.)

Background: Chemical exchange saturation transfer (CEST) magnetic resonance imaging can provide surrogate biomarkers for disease diagnosis. However, endogenous CEST effects are always diluted and contaminated by competing effects, which results in unwanted signal contributions that lessen the specificity of CEST to underlying biochemical exchange processes. The aim of this study was to examine a method for the accurate quantification of CEST effects., Methods: A Markov chain Monte Carlo (MCMC)-based Bayesian inference approach was proposed to estimate the exchange parameters, and CEST effects could be fitted using these estimations. This approach was tested in Bloch simulation and ischemic stroke rat experiments, and its performance was evaluated using quantification maps and numerical metrics., Results: With 12 groups of simulations, the MCMC method achieved satisfactory fittings on both 2-pool and 5-pool models. The sum of squares error values and the root mean square error of the fitted Z-spectra were smaller than 10 -3 , and the coefficient of determination (R-squared) values were close to 1. The corresponding CEST quantification M T R R e x C E S T spectra were also well fitted and successfully separated the mixed CEST effects. The estimated parameters showed little bias relative to the ground truth, with errors between the true and estimated values of each parameter of less than 0.5%. In the animal experiments, M T R R e x A m i d e fitted using the MCMC method showed obvious contrast between ischemic and contralateral regions at the early stage. Compared with other quantification methods, it displayed the highest contrast-to-noise ratios (3.9, 2.73, and 3.93) and the lowest coefficient of variation values (0.181, 0.2224, and 0.2897) in all three stroke periods., Conclusions: The MCMC method provided an efficient approach for parameter estimation and CEST effect quantification. The method may therefore be useful in achieving an accurate pathological diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-313/coif). The authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)-expressing hematopoietic stem cells (HSCs) are genetically engineered for bone-targeted delivery of the transforming growth factor beta (TGF-β) small-molecule inhibitor SB-505124 (SB@HSCs-PD-1). Intriguingly, compared to anti-PD-L1 monoclonal antibodies, as "living drugs", HSCs-PD-1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD-1 molecules. The SB released from HSCs-PD-1 competitively bound to TGF-β receptors on CD4 + T cells and facilitate CD4 + T cell differentiation to helper T (T H )1 and T H 2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs-PD-1 can block programmed death-ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti-tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Recent studies showed that lipid metabolism reprogramming contributes to tumorigenicity and malignancy by interfering energy production, membrane formation, and signal transduction in cancers. HNSCCs are highly reliant on aerobic glycolysis and glutamine metabolism. However, the mechanisms underlying lipid metabolism reprogramming in HNSCCs remains obscure. The present review summarizes and discusses the "vital" cellular signaling roles of the lipid metabolism reprogramming in HNSCCs. We also address the differences between HNSCCs regions caused by anatomical heterogeneity. We enumerate these recent findings into our current understanding of lipid metabolism reprogramming in HNSCCs and introduce the new and exciting therapeutic implications of targeting the lipid metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miao, Wang, Chen, Ding, Wu, Pan, Ji, Ye and Xiang.)

The critical pathogenesis of type 1 diabetes (T1D)/type 2 diabetes (T2D) is the physical status, mass, and function of pancreatic β cells. Mammalian STE20-like protein 1 kinase (MST1) plays vital roles in the apoptosis and insulin secretion of β cells. Here, we discovered a novel, potent, and selective MST1 inhibitor 19 (IC 50 = 23 nM), which inhibited the phosphorylation of MST1-protected β cells from the damage of inflammatory cytokines in vitro. In vivo, it displayed acceptable pharmacokinetic properties in different species. In the STZ-induced T1D/T2D mouse models, both monotherapy of 19 and in combination with metformin led to the decline of fasting blood glucose and showed protective effect of β cells. In addition, the combination of 19 and metformin decreased the hemoglobin A1c level. Together, our study suggested that 19 might be a useful pharmacological tool to study MST1-mediated physiology and pathology as well as a potential drug candidate for diabetes.

The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention., Competing Interests: The authors declare no competing interests., (© 2022 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

As a promising noninvasive medical imaging technique, bioluminescence tomography (BLT) dynamically offers three-dimensional visualization of tumor distribution in living animals. However, due to the high ill-posedness caused by the strong scattering property of biological tissues and the limited boundary measurements with noise, BLT reconstruction still cannot meet actual preliminary clinical application requirements. In our research, to recover 3D tumor distribution quickly and precisely, an adaptive Newton hard thresholding pursuit (ANHTP) algorithm is proposed to improve the performance of BLT. The ANHTP algorithm fully combines the advantages of sparsity constrained optimization and convex optimization to guarantee global convergence. More precisely, an adaptive sparsity adjustment strategy was developed to obtain the support set of the inverse system matrix. Based on the strong Wolfe line search criterion, a modified damped Newton algorithm was constructed to obtain optimal source distribution information. A series of numerical simulations and phantom and in vivo experiments show that ANHTP has high reconstruction accuracy, fast reconstruction speed, and good robustness. Our proposed algorithm can further increase the practicality of BLT in biomedical applications.

Increasing investigations have focused on long non-coding RNAs (lncRNAs) in various human diseases, including acute myocardial infarction (AMI). Although lncRNA HOTTIP has been identified to play an important role in coronary artery diseases, its role and specific mechanism in AMI remain unclear. To investigate the potential role of HOTTIP in MI, HOTTIP expression in hypoxia-treated cardiomyocytes and myocardial tissues of MI mice was evaluated. The potential targets of HOTTIP and miR-92a-2 were predicted using Starbase and Targetscan. To further determine the cardio-protective effects of HOTTIP in vivo, si-HOTTIP and miR-92a-2 mimics were individually or co-injected into mice through intramyocardial injection. Moreover, their roles were further confirmed in rescue experiments. HOTTIP was significantly upregulated in ischemic myocardium of MI mice and hypoxia-induced cardiomyocytes. Moreover, HOTTIP knockdown markedly promoted cardiomyocyte growth and inhibited cardiomyocyte apoptosis in vitro. Luciferase reporter assay showed that HOTTIP could directly sponge miR-92a-2 to negatively regulate miR-92a-2 expression. In addition, c-Met was identified as a direct target of miR-92a-2, and their correlation was confirmed by luciferase reporter assay. MiR-92a-2 overexpression significantly enhanced the protective effect of HOTTIP knockdown against AMI through partially inhibiting c-Met expression. Our results demonstrated that HOTTIP downregulation attenuated AMI progression via the targeting miR-92a-2/c-Met axis and suggested that HOTTIP might be a potential therapeutic target for AMI., (© 2022. The Author(s).)

A great number of patients with Coronavirus Disease 2019 (COVID-19) experience olfactory dysfunction, typically of a short duration and with a high incidence rate, during the early stages of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This kind of olfactory dysfunction appears more likely in young people and women. This study presents a review of the clinical features and pathogenic mechanism of the olfactory dysfunction related to SARS-CoV-2 infection, aiming to provide a clinical reference for the diagnosis, differential diagnosis, treatment, and prevention of olfactory dysfunction in COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mao, Ye, Fan, Wu, Wang, Shen, Shi and Xiang.)

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., (© 2021. The Author(s).)

3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized from resveratrol (Res) and 3-O-β-D-galactose (Gal) in our previous study. In order to improve the pH sensitivity and bioavailability of Gal-Res, Gal-Res nanoparticles (Gal-Res NPs) were prepared using polydopamine (PDA) as a drug carrier. The drug loading (DL %) and entrapment efficiency (EE %) of Gal-Res NPs were 46.80% and 88.06%. The average particle size, polydispersity index (PDI), and Zeta potential of Gal-Res NPs were 179.38 ± 2.83 nm, 0.129 ± 0.013, and - 28.05 ± 0.36 mV, respectively. The transmission electron microscope (TEM) showed that Gal-Res NPs had uniform spherical morphology. Compared with the fast release of raw Gal-Res, the in vitro release of Gal-Res NPs was slow and pH-sensitive. The results of the blood vessel irritation and hemolysis test demonstrated that Gal-Res NPs had good hemocompatibility. The pharmacokinetics study in rats showed that area under the curve of plasma drug concentration time (AUC 0→600 ) and half-life (t 1/2 ) of Gal-Res NPs were enhanced 1.82-fold and 2.19-fold higher than those of raw Gal-Res. The in vivo biodistribution results showed that Gal-Res NPs were more distributed in liver tissue than Gal-Res. Gal-Res NPs with high bioavailability and liver accumulation were hopeful drug delivery systems (DDS) to treat liver diseases., (© 2021. American Association of Pharmaceutical Scientists.)

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor ( S )-18 . In the biochemical assay, ( S )-18 inhibits PI3Kδ (IC 50 = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). ( S )-18 also achieves good selectivity over other protein kinases in the kinome ( S -score (35) = 0.015). In the cell, ( S )-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, ( S )-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC 50 > 10 μM). In vivo, ( S )-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that ( S )-18 might be a new potential therapeutic candidate for COPD.

Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117 h (>20-fold). In the 150 days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8 days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 μM (mice) and 1.6 μM (rats) at 12 h, which is over 200-fold higher than the EC 50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy., Supplementary Information: The online version contains supplementary material available at 10.1186/s43556-020-00018-9., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.

There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T315I mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I. 24 exhibited IC 50 values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI 50 at single digit nM. In cellular context, 24 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis as well as arrested cell cycle at G0/G1 phase. In the in vivo study, 50 mg/kg/day dosage of 24 displayed TGI of 52% in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC 50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (k inact /K i ) of 0.01 μM -1 s -1 . Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC 50  < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC 50 : 7 nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC 50 : <30 nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC 50 : 46 nM) and c-KIT kinase (IC 50 : 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 μM among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery.

Objective: To test the hypotheses that brain networks of patients with epilepsy differ from that of healthy controls and functional interactions in the brain are correlated to the duration of epilepsy., Method: The present study recorded Magnetoencephalography (MEG) data from twenty patients with epilepsy and twenty healthy controls, constructed the whole functional brain network based on phase lag index (PLI), compared the differences in functional connectivity and network measures between patients with epilepsy and healthy controls, and analyzed the correlation between network measures and the duration of epilepsy., Results: The patients with epilepsy showed significant increase in mean functional connectivity in the alpha band, gamma band and ripple band, significant increase in mean clustering coefficient in the theta band, beta band and ripple band, significant increase in average shortest path length in the theta band and alpha band. Only in the alpha band, a significant negative correlation between mean clustering coefficient and the duration of epilepsy was detected., Conclusions: Our results indicated that the alterations of functional brain network are related to a functional imbalance that resulted from epileptic activity and the brain network of patients with epilepsy become more pathological over time., (Copyright © 2016 Elsevier B.V. All rights reserved.)

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.