Tribbles pseudokinase 3 promoted renal fibrosis by regulating the expression of DNA damage-inducible transcript 3 in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB, among differentially expressed genes (DEGs) in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production inMPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.

ENO1 contributes to the gemcitabine resistance of pancreatic cancer through the YAP1 signaling pathway.

Pancreatic cancer (PC), a leading cause of cancer-related deaths, has a 5-year survival rate of approximately 10%. α-Enolase (ENO1) is a junction channel protein involved in tumor cell apoptosis and chemoresistance. However, the role of ENO1 in PC remains unclear. The expression and prognosis of ENO1 levels were determined in PC using public databases based on The Cancer Genome Atlas (TCGA) data sets. Cell viability, half maximal inhibitory concentration (IC50), autophagy, apoptosis, and autophagy markers were examined using cell counting kit-8 (CCK-8), transmission electron microscope, flow cytometry assays, and immunoblot, respectively. Using the Gene Expression Omnibus (GEO) and TCGA data sets, we found that ENO1 was significantly enriched in PC tumor tissues, and high expression levels of ENO1 were associated with an unfavorable prognosis. Whereas ENO1 silencing suppressed proliferation, autophagy, and induced cell apoptosis in PC cells, and inhibited tumor growth in vivo. Mechanistically, knockdown of ENO1 enhanced cellular cytotoxicity of gemcitabine (GEM), as well as reducing the expression of yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway in vitro. YAP1 promoted autophagy and protected PC cells from GEM-induced apoptotic cell death. Furthermore, YAP1 overexpression attenuated the inhibition effects of ENO1 silencing. Our results suggest that ENO1 overexpression promotes cell growth and tumor progression by increasing the expression of YAP1 in PC. Further studies are required to understand the detailed mechanisms between ENO1 and YAP1 in PC.

Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov).

Covalent kinase inhibitors (CKIs) hold great promise for drug development. However, examples of computationally guided design of CKIs are still scarce. Here, we present an integrated computational workflow (Kin-Cov) for rational design of CKIs. The design of the first covalent leucine-zipper and sterile-α motif kinase (ZAK) inhibitor was presented as an example to showcase the power of computational workflow for CKI design. The two representative compounds, 7 and 8, inhibited ZAK kinase with half-maximal inhibitory concentration (IC50) values of 9.1 and 11.5 nM, respectively. Compound 8 displayed an excellent ZAK target specificity in Kinome profiling against 378 wild-type kinases. Structural biology and cell-based Western blot washout assays validated the irreversible binding characteristics of the compounds. Our study presents a rational approach for the design of CKIs based on the reactivity and accessibility of nucleophilic amino acid residues in a kinase. The workflow is generalizable and can be applied to facilitate CKI-based drug design.

Edge-oriented phosphatizing engineering of 2D Ni-MOFs with a tailored d-band center for boosting catalytic activity.

Metal-organic framework (MOF)-based heterostructures have aroused widespread interest owing to their extensive compositional tunability and interesting catalytic properties. However, the precise edge-oriented growth of transition metal compounds at the edges of 2D MOFs to construct edge mode heterostructures remains a great challenge due to their inherent thermodynamic instability. Here, edge-oriented growth of Ni2P at the edges of a 2D Ni-MOF was achieved for the first time by precisely tuning the phosphorus source content and phosphating temperature. Owing to the formation of the edge mode Ni-MOF/Ni2P heterostructure, the as-prepared heterostructure showed upregulated d-band center, more robust 4-nitrophenol (4-NP) adsorption capacity, lowered energy barrier of the rate-determining step (RDS), and higher specific surface area, resulting in the best performance of the hydrogenation reduction of 4-NP to 4-aminophenol (4-AP) in the presence of non-precious metal catalysts.

The ultrathin palladium nanosheets for sensitive and visual Hg2+ detection in the food chain.

The detection of mercury, one of the ten most dangerous chemicals, is significant to provide helpful information for assessing mercury toxicity and health risks. However, it is a challenge to explore simple, sensitive, accurate, and cheap Hg2+ detection methods. Noble metal nanomaterials are used for Hg2+ detection by the colorimetric method widely. Still, the pure noble metal materials' detection limit of Hg2+ is high, and sensitivity enhancement usually requires further complex modification. Here, we use a facile one-step route to synthesize ultra-thin two-dimensional palladium nanosheets (PdNS), which have high selectivity and sensitivity for Hg2+ detection by colorimetric method with a low detection limit (0.55 ppb). The detection of Hg2+ by PdNS involves multiple mechanisms, including the formation of amalgam and PdO to improve the peroxidase-mimic activity of PdNS and PdNS motor function to increase its collision probability with the detection reactant. The PdNS can be used to detect Hg2+ in various actual samples. The detection results are highly consistent with the data obtained by the atomic fluorescence spectrometer (AFS). Then, we developed a Hg2+ detection kit, which can realize simple, sensitive, and accurate Hg2+ detection by naked eye or cellphone at a meager cost (0.3 dollars each sample).

Effect of temperature on PTEs deportment and ecological risks of the biochars obtained from sewage sludge.

Sewage sludge-derived biochars (SSBCs) were obtained at temperatures of 300, 500, and 700 °C to investigate the potentially toxic elements (PTEs) behaviors and assess the environmental acceptability for the possible application in the environment. Results indicated that PTEs exhibited diversely in the distribution of chemical speciation, while all elements tended to be immobilized in biochar matrix and the total amount elevated during the pyrolysis. The risk assessment of biochars implied a low degree of environmental risk for the utilization of SSBCs prepared at high temperatures. In addition, higher pyrolysis temperature alleviated the inhibition on the early seedling growth of Triticum aestivum L., with root elongation more sensitive to the biochar addition. PTEs, especially Cr, contributed much to the phytotoxicity of biochars as revealed by the principle component analysis (PCA) and leaner correlation analysis. Findings from this work illustrated that SSBCs prepared at higher temperatures might be more conductive to a wide range of applications with acceptable environmental risk.

Cyclic coupling of photocatalysis and adsorption for completely safe removal of N-nitrosamines in water.

The incomplete removal of N-nitrosamines in water through current degraded techniques and the carcinogenicity of N-nitrosamines call for alternative complete and safe removal approaches. Here, we describe a cyclic coupling process of photocatalysis and adsorption enabling N-nitrosamines in water thoroughly and safely removed. Among them, the immobilized TiO2/Ti photocatalyst degraded N-nitrosamines into primary and secondary amines up to 100% by attacking on nitrosyl nitrogen via •OH originated from its nanowire film morphology. Furthermore, the affinity of HY zeolite to primary and secondary amines led to efficient adsorption through corresponding to Lagergren adsorption rate equation of second order. And then the cyclic coupling process of photocatalysis and adsorption realized complete and safe removal of N-nitrosamines with various concentration ranging from 0.1 mM to 1 mM in water, significantly higher than the existing reports on the removal rate of N-nitrosamines and the formation potential of N-nitrosamines. This study will lead to new avenues for complete and safe eliminaton of hardly degradable hazardous substances in water.

The influence of modified molecular (D/L-serine) chirality on the theragnostics of PAMAM-based nanomedicine for acute kidney injury.

Acute kidney injury (AKI) is a severe clinical disease with extremely high morbidity and mortality. It is challenging to find a simple method for early detection of AKI and monitoring the treatment results. Renal tubular damage and inflammation are early events in AKI. Renal tubular damage is conducive to the accumulation of small-sized nanoparticles in the kidney, and inflammation is related to the excessive production of H2O2. Recent studies proved that chiral molecule modification of nanomaterials is a powerful strategy to regulate their biodistribution. Thus, L-serine and D-serine modified poly(amidoamine) (PAMAM) dendrimers were synthesized and used as fluorescent probe (NPSH) carriers to obtain L-SPH and D-SPH, respectively. D-SPH has a strong accumulation capability in the kidney of AKI mice. Then, the H2O2 fluorescent probe can detect the excessively produced H2O2 to generate fluorescence to diagnose AKI. Subsequently, the anti-inflammatory drug manganese pentacarbonyl bromide (CORM) was loaded in D-SPH to obtain D-SPHC with AKI theragnostic functions. Simultaneously, the D-SPHC fluorescence signal intensity change during the treatment can be used to monitor the recovery process. This study is the first report of chiral materials used in the diagnosis and treatment of AKI.

MEKK3 in hybrid snakehead (Channa maculate ♀ ×Channa argus ♂): Molecular characterization and immune response to infection with Nocardia seriolae and Aeromonas schubertii.

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is a serine/threonine protein kinase that acts as a key regulator and is widely involved in various innate and acquired immune signaling pathways. In this study, we first cloned the complete open reading frame (ORF) of the MEKK3 gene (named CcMEKK3) in a hybrid snakehead (Channa maculate ♀ × Channa argus ♂). The full-length ORF of CcMEKK3 is 1851 bp, and encodes a putative protein of 616 amino acids containing a serine/threonine kinase catalytic (S-TKc) domain and a Phox and Bem1p (PB1) domain. A sequence alignment and phylogenetic tree analysis showed that CcMEKK3 is highly conserved relative to the MEKK3 proteins of other teleost species. CcMEKK3 was constitutively expressed in all the healthy hybrid snakehead tissues tested, with greatest expression in the immune tissues, such as the head kidney and spleen. The expression of CcMEKK3 was usually upregulated in the head kidney, spleen, and liver at different time points after infection with Nocardia seriolae or Aeromonas schubertii. Similarly, the dynamic expression levels of CcMEKK3 in head kidney leukocytes after stimulation revealed that CcMEKK3 was induced by LTA, LPS, and poly(I:C). In the subcellular localization analysis, CcMEKK3 was evenly distributed in the cytoplasm of HEK293T cells, and its overexpression significantly promoted the activities of NF-κB and AP-1. These results suggest that CcMEKK3 is involved in the immune defense against these two pathogens, and plays a crucial role in activating the NF-κB and MAPK signaling pathways.

Mg2TiO4 spinel modified by nitrogen doping as a Visible-Light-Active photocatalyst for antibacterial activity.

Nitrogen doped Mg2TiO4 spinel, i.e. Mg2TiO4-xNy, has been synthesized and investigated as a photocatalyst for antibacterial activity. Mg2TiO4-xNy demonstrates superior photocatalytic activity for E. coli disinfection under visible light illumination (λ ≥ 400 nm). Complete disinfection of E. coli at a bacterial cell density of 1.0 × 107 CFU mL-1 can be achieved within merely 60 min. Mg2TiO4-xNy is capable of generating superoxide radicals (•O2 -) under visible light illumination which are the reactive oxygen species (ROSs) for bacteria disinfection. DFT calculations have verified the importance of nitrogen dopants in improving the visible light sensitivity of Mg2TiO4-xNy. The facile synthesis, low cost, good biocompatibility and high disinfection activity of Mg2TiO4-xNy warrant promising applications in the field of water purification and antibacterial products.

HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones.

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.

Immunomodulatory activity of puerarin in RAW264.7 macrophages and cyclophosphamide-induced immunosuppression mice.

CONTEXT: Puerarin, a natural isoflavone extracted from Radix puerariae, is famous for treating various cardiovascular and cerebrovascular diseases. However, little is known about its direct immunomodulatory activity. OBJECTIVE: This study was designed to investigate the in vitro and in vivo immunomodulatory effects of Radix puerariae by using the murine monocyte-macrophage cell line RAW264.7 and immunosuppressed cyclophosphamide-induced mice. METHODS: MTT and neutral red phagocytosis assays were conducted to evaluate the in vitro immunomodulatory activities of puerarin on cell viability and phagocytosis by measuring the proliferation, phagocytic, nitric oxide (NO) ability, and TNF-α production ability of stimulated and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Immunosuppressed cyclophosphamide-induced mice were used to evaluate the in vivo immunomodulatory activities of puerarin by measuring IL-4 and IFN-γ, the serum half hemolysis value, spleen and thymus index, and proliferation assay for splenic lymphocytes. RESULTS AND DISCUSSION: Results showed that puerarin improves immunomodulatory activity by increasing cell proliferation, cell phagocytosis, and NO secretion in RAW264.7 macrophages and reduces the abnormal immunologic activity by decreasing cell phagocytosis and NO secretion in LPS-stimulated RAW264.7 macrophages. In addition, puerarin enhanced the immunologic activity of cyclophosphamide-induced immunosuppression mice by increasing the secretion of NO, IFN-γ, and IL-4, the serum half hemolysis value (HC50), the spleen and thymus index, and proliferation for splenic lymphocytes. CONCLUSION: Puerarin exhibited an upregulated immunomodulatory effect on RAW264.7 macrophages and immunosuppression mice. In addition, puerarin had a downregulated immunomodulatory effect on RAW264.7 macrophages. The results suggest that puerarin could be a promising immunomodulator to assist in the treatment of tumors.

Two types of TNF-α and their receptors in snakehead (Channa argus): Functions in antibacterial innate immunity.

Tumor necrosis factor-α (TNF-α) is a pluripotent mediator of pro-inflammatory and antimicrobial defense mechanisms and a regulator of lymphoid organ development. Although two types of TNF-α have been identified in several teleost species, their functions in pathogen infection remain largely unexplored, especially in pathogen clearance. Herein, we cloned and characterized two types of TNF-α, termed shTNF-α1 and shTNF-α2, and their receptors, shTNFR1 and shTNFR2, from snakehead (Channa argus). These genes were constitutively expressed in all tested tissues, and were induced by Aeromonas schubertii and Nocardia seriolae in head kidney and spleen in vivo, and by lipoteichoic acid (LTA), lipopolysaccharides (LPS), and Polyinosinic-polycytidylic acid [Poly (I:C)] in head kidney leukocytes (HKLs) in vitro. Moreover, recombinant shTNF-α1 and shTNF-α2 upregulated the expression of endogenous shTNF-α1, shTNF-α2, shTNFR1, and shTNFR2, and enhanced intracellular bactericidal activity, with shTNF-α1 having a greater effect than shTNF-α2. These findings suggest important roles of fish TNFα1, TNFα2, and their receptors in bacterial infection and pathogen clearance, and provide a new insight into their function in antibacterial innate immunity.

Bacteria-induced IL-1ß and its receptors in snakehead (Channa argus): Evidence for their involvement in antibacterial innate immunity.

As a central pro-inflammatory cytokine, interleukin-1ß (IL-1ß) plays critical roles in the inflammatory response, pathogen infection, and immunological challenges in mammals. Although fish IL-1ß has been confirmed to participate in inflammatory response to pathogen infection, few studies have been performed to characterize the antibacterial and bactericidal functions of fish IL-1ß. In this study, snakehead (Channa argus) IL-1ß (shIL-1ß) and its receptors, shIL-1R1 and shIL-1R2, were cloned and functionally characterized. ShIL-1ß contained the IL-1 family signature domain, and a potential cutting site at Asp96 that presented in all vertebrate IL-1ß sequences. ShIL-1R1 had three extracellular IG-like domains and one intracellular signal TIR domain, while shIL-1R2 had three extracellular IG-like domain but lacked the intracellular signal TIR domain. ShIL-1ß, shIL-1R1, and shIL-1R2 were constitutively expressed in all tested tissues, and their expressions could be induced by Aeromonas schubertii and Nocardia seriolae in the head kidney and spleen in vivo, and by LTA, LPS, and Poly (I:C) in head kidney leukocytes (HKLs) in vitro. Moreover, recombinant shIL-1ß upregulated the expression of endogenous shIL-1ß, shIL-R1, and shIL-R2 in snakehead HKLs, and enhanced intracellular bactericidal activity. Taken together, this study found that, like IL-1ß and its receptors in mammals, shIL-1ß and its receptors play crucial roles in antibacterial innate immunity. This provides new insight into the evolution of IL-1ß function in vertebrates.

Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors.

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.

Integrating metabolomics and physiological analysis to investigate the toxicological mechanisms of sewage sludge-derived biochars to wheat.

Effects of sewage sludge biochars (SSBCs) on the growth of wheat and the specific toxicological mechanisms were investigated from a metabolic perspective for better ecological risk assessment. We observed that conversion of sludge to biochar remarkably changed the properties, and also caused a significant (p < 0.05) reduction of the toxicity towards wheat. Wheat growth under exposure to SSBCs was influenced by the pyrolysis temperature (300 °C, 500 °C and 700 °C), with root length being promoted by SSBCs prepared at higher temperatures (500 °C and 700 °C). In addition to the contaminants, including polycyclic aromatic hydrocarbons (PAHs) and potentially toxic elements (PTEs) detected in SSBCs, the morphological characteristics of biochars contributed substantially to the wheat growth. Metabolomics analysis revealed the remarkable differences in the metabolic profiles among the control (CK), SS300- and SS700-treated samples. The toxicological mechanisms involved were found to be associated with the regulation of metabolisms pathways of protein, fatty acids and carbohydrates, among which protein metabolism was most affected by SSBCs. This work presents an innovative concept that SSBCs produced at a proper temperature may minimize the toxic effects on plant growth by regulating the metabolic fluxes in vivo.

Biochar accelerates PAHs biodegradation in petroleum-polluted soil by biostimulation strategy.

Sawdust and wheat straw biochars prepared at 300°C and 500°C were applied to petroleum-polluted soil for an 84-day incubation to estimate their effectiveness on polycyclic aromatic hydrocarbons (PAHs) removal. Biochars alone were most effective at reducing PAHs contents. However, adding biochar to soils in company with NaN3 solution resulted in a decreasing trend in terms of PAHs removal, which was even lower than treatment CK without biochar. Moreover, it was discovered by PCR-DGGE files and sequencing analysis that the predominant bacterial diversity slightly decreased but the abundance of some specific taxa, including PAHs degraders, was promoted with biochar input. These results highlighted the potential of biochar application on accelerating PAHs biodegradation, which could be attributed to the properties of biochars that benefit for making the amended soil a better habitat for microbes. The impacts of biochar preparation and pollutants nature on PAHs removal were also determined. Significant reduction in the PAHs contents was detected when adding biochar prepared at a high temperature (500°C), while the feedstocks of biochar showed little effect on PAHs removal. Due to the high hydrophobicity of aromatic rings, high-molecular weight PAHs were found much more resistant to microbial degradation in comparison with low-molecular weight PAHs.

Structural pharmacological studies on EGFR T790M/C797S.

Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Gö6976 and T790M + Gö6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Gö6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration.

Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.

Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML).

BCR gene fused ABL kinase is the critical driving force for the Philadelphia Chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) and has been extensively explored as a drug target. With a structure-based drug design approach we have discovered a novel inhibitor CHMFL-074, that potently inhibits both the native and a variety of clinically emerged mutants of BCR-ABL kinase. The X-ray crystal structure of CHMFL-074 in complex with ABL1 kinase (PDB ID: 5HU9) revealed a typical type II binding mode (DFG-out) but relatively rare hinge binding. Kinome wide selectivity profiling demonstrated that CHMFL-074 bore a high selectivity (S score(1) = 0.03) and potently inhibited ABL1 kinase (IC50: 24 nM) and PDGFR α/ß (IC50: 71 nM and 88 nM). CHMFL-074 displayed strong anti-proliferative efficacy against BCR-ABL-driven CML cell lines such as K562 (GI50: 56 nM), MEG-01 (GI50: 18 nM) and KU812 (GI50: 57 nM). CHMFL-074 arrested cell cycle into the G0/G1 phase and induced apoptosis in the Ph+ CML cell lines. In addition, it potently inhibited the CML patient primary cell's proliferation but did not affect the normal bone marrow cells. In the CML cell K562 inoculated xenograft mouse model, oral administration of 100 mg/kg/d of CHMFL-074 achieved a tumor growth inhibition (TGI) of 65% without exhibiting apparent toxicity. As a potential drug candidate for fighting CML, CHMFL-074 is under extensive preclinical safety evaluation now.