Research Progress in Nanofluid-Enhanced Oil Recovery Technology and Mechanism.

Nanofluid-enhanced oil recovery (EOR) technology is an innovative approach to enhancing oil production in oilfields. It entails the dispersion of nanoparticles within a fluid, strategically utilizing the distinctive properties of these nanoparticles (NPs) to engage with reservoir rocks or crude oil, resulting in a significant enhancement of the oil recovery rate. Despite the notable advantages of nanofluid EOR technology over conventional oil recovery methods such as binary and ternary flooding, practical implementations continue to grapple with a range of pressing challenges. These challenges encompass concerns regarding the economic viability, stability, and adaptability of nanomaterials, which pose significant barriers to the widespread adoption of nanofluid EOR technology in the oil field. To tackle these challenges, addressing the current issues may involve selecting simpler and more readily available materials coupled with straightforward material modification techniques. This approach aims to more effectively meet the requirements of large-scale on-site applications. Within this framework, this review systematically explores commonly employed nanofluids in recent years, including inorganic nanofluids, organic nanofluids, and composite nanofluids. It categorizes the research advancements in optimizing modification techniques and provides a comprehensive overview of the mechanisms that underpin nanofluid EOR technology and its practical applications in oilfields. This comprehensive review aims to offer valuable references and serve as a solid foundation for subsequent research endeavors.

Discovery of dihydropyridinone derivative as a covalent EZH2 degrader.

EZH2 is overexpressed in multiple types of cancer and high expression level of EZH2 correlates with poor prognosis. Besides the regulation of H3K27 trimethylation, EZH2 itself regulates its downstream proteins in a PRC2- and methylation-independent way. Starting from an approved EZH2 inhibitor EPZ-6438, we used covalent drug design and medicinal chemistry approaches to discover a novel covalent EZH2 degrader 38, which forms a covalent bond with EZH2 Cys663 and showed strong biochemical activities against EZH2 WT and mutants. Compound 38 exhibited potent antiproliferation effects against both B-cell lymphoma and TNBC cell lines by reducing the levels of H3K27me3 and EZH2. The mass spectrometry, washout and competition experiments confirmed the covalent binding of 38 to EZH2. This study demonstrates that covalent EZH2 degraders could provide an opportunity for the development of promising new drug candidates.

Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3Kγ/δ dual inhibitor.

Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model.

Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.

Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC50 = 4.7 nM), which displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. The crystal structure demonstrates that 16 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. 16 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC50 = 28 nM). In addition, it inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants. In vivo, 16 inhibits 2-HG level in a HT1080 xenograft mouse model. Our study suggested that 16 would be a new pharmacological tool to study IDH1 mutant-related pathology and the covalent binding mode provided a novel approach for designing irreversible IDH1 inhibitors.

Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment.

Although rat sarcoma viral oncogene homolog (RAS) mutations occur in about 30% of solid tumors, targeting RAS mutations other than KRAS-G12C is still challenging. As an alternative approach, developing inhibitors targeting RAF, the downstream effector of RAS signaling, is currently one of the main strategies for cancer therapy. Selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-V600E inhibitors Vemurafenib, Encorafenib, and Dabrafenib have been approved by FDA and received remarkable clinical responses, but these drugs are ineffective against RAS mutant tumors due to limited inhibition on dimerized RAF. In this study, we developed a highly potent pan-RAF inhibitor, IHMT-RAF-128, which exhibited similarly high efficacies in inhibiting both partners of the RAF dimer, and showed potent anti-tumor efficacy against a variety of cancer cells harboring either RAF or RAS mutations, especially Adagrasib and Sotorasib (AMG510) resistant-KRAS-G12C secondary mutations, such as KRAS-G12C-Y96C and KRAS-G12C-H95Q. In addition, IHMT-RAF-128 showed excellent pharmacokinetic profile (PK), and the bioavailability in mice and rats were 63.9%, and 144.1%, respectively. Furthermore, IHMT-RAF-128 exhibited potent anti-tumor efficacy on xenograft mouse tumor models in a dose-dependent manner without any obvious toxicities. Together, these results support further investigation of IHMT-RAF-128 as a potential clinical drug candidate for the treatment of cancer patients with RAF or RAS mutations.

Identification and characterization of the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes by LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements.

Moscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC-Orbitrap-MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.

Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors.

Colony stimulating factor 1 receptor kinase (CSF1R) plays an integral role in tumor-associated macrophage repolarization and has emerged as a novel therapeutic target for cancer immunotherapy. Most of the current CSF1R kinase inhibitors lack selectivity between CSF1R kinase and other type III growth factor receptor members. Herein, we report a potent and selective CSF1R inhibitor 18h, which displays an IC50 value of 5.14 nM against CSF1R and achieves selectivity over other type III receptor tyrosine kinases (>38-fold). 18h inhibits the phosphorylation of CSF1R and its downstream signaling pathway in RAW264.7, THP-1, and M-NFS-60 cells. Treatment with this compound leads to alteration of the macrophage polarization in RAW264.7 macrophages in a dose-dependent manner. In vivo, 18h demonstrates acceptable pharmacokinetic profiles and suppresses the tumor growth in a mouse xenograft model inoculated with M-NFS-60 cells.

PEG-Bottlebrush Stabilizer-Based Worm-like Nanocrystal Micelles with Long-Circulating and Controlled Release for Delivery of a BCR-ABL Inhibitor against Chronic Myeloid Leukemia (CML).

Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene-co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053.

A Durable Magnetic Superhydrophobic Melamine Sponge: For Solving Complex Marine Oil Spills.

The problem of offshore oil leakage has wreaked havoc on the environment and people's health. A simple and environmentally friendly impregnation method combined with marine mussel bionics was used to address this issue. Using the viscosity of polydopamine (PDA), nano- Fe3O4 and WS2 adhered to the framework of the melamine sponge (MS), and then the magnetic sponge was modified with n-octadecanethiol (OTD), and finally the superhydrophobic magnetic melamine sponge (mMS) was prepared. The modified sponge has superhydrophobicity (WCA, 156.8° ± 1.18°), high adsorbability (40~100 g°g−1), recyclability (oil adsorbability remains essentially unchanged after 25 cycles), efficient oil−water separation performance (>98%), and can quickly separate oil on the water's surface and underwater. Furthermore, the modified sponge exhibits excellent stability and durability under harsh operating conditions such as strong sunlight, strong acid, strong alkali, and high salt, and can control the direction of the sponge's movement by loading a magnetic field. To summarize, mMS has many potential applications as a new magnetic adsorption material for dealing with complex offshore oil spill events.

A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities.

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF3-phenyl triphenylphosphonium-based PBA conjugate (53) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC50 value of 2.22 µM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.

Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2.

Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.

LC-MS/MS method for determination of kansuinine a in rat plasma and its application to a rat pharmacokinetic study.

Kansuinine A is a macrocyclic jatrophane diterpene isolated from the plant Euphorbia kansui Liou. It exhibits many pharmacological activities including cytoxic, antitumor, antiallergic and proinflammatory effects. In the present study, a simple and sensitive LC-MS/MS method was established and validated for the determination of kansuinine A in rat plasma. After methanol-mediated protein precipitation, chromatographic separation was achieved on an Acquity BEH C18 column (2.1 × 100 mm, 1.7 µm) using acetonitrile and 0.1% formic acid in water as mobile phase by gradient elution. Kansuinine A and IS were quantified in negative multiple reaction monitoring mode with ion transitions at m/z 731.1-693.2 for kansuinine A and m/z 723.2-623.1 for IS. The method showed excellent linearity over the range 1-500 ng/ml. The intra- and inter-day precisions (relative standard deviation) were 2.13-4.28 and 3.83-7.67%, respectively, whereas accuracy (relative error) ranged from -4.17 to 3.73%. The extraction recovery, stability and matrix effect met the requirement of the regulations issued by the US Food and Drug Administration. The validated method was successfully applied to the pre-clinical pharmacokinetic study of kansuinine A in rats after oral administration (20 mg/kg) and intravenous administration (2 mg/kg). This study provides valuable reference for the further study of E. kansui liou, especially for the drug development and clinical application of kansuinine A.

Syntheses of a Hyperbranched Polymer and Its Performance on Enhanced Oil Recovery.

A hyperbranched carboxylate-type polymer was synthesized through esterification and carboxymethylation, and its performance on enhanced oil recovery was experimentally evaluated. The optimum condition for esterification was 8 h at 120°C, where 3% PTSA as the catalyst and 9:1 mol ratio of the AB2 intermediate and trimethylolpropane were used. The optimum condition for carboxymethylation was 4 h at 80°C. The critical micelle concentration of the hyperbranched polymer was 433.63 mg/L, the Krafft point was 5°C, and the surface tension was lowered to 28 mN/m. In the range of 400-500 mg/L concentration, the adsorption onto the oil sand surface achieved equilibrium, and micellar solubilization reached 600 ml/mol. The interfacial tension can be lowered to a level of 10-2 mN/m by the single use of the hyperbranched polymer, and the value further decreased to a level of 10-3 mN/m while being formulated with sodium dodecylsulfate or NaOH. Oil recovery of water flooding was further enhanced by the single use of a hyperbranched polymer or the combination of hyperbranched polymer/sodium dodecylsulfate. The latter exhibited more prosperous advantages in low-permeability reservoirs.

Fabrication of Superhydrophobic SA-CeO2@Cu Mesh and Its Application in Oil-Water Separation.

CeO2 was synthesized by the co-precipitation method on the Cu mesh substrate and modified the surface of CeO2@Cu mesh by stearic acid (SA). The superhydrophobic behavior was ascribed to the combination of hierarchical micro-nanostructure of CeO2 and the hydrophobic alkyl groups from SA. The SA-CeO2@Cu mesh had antiacid and base stability and excellent durability as well as high separation efficiency. The separation efficiency can be up to 98.0% after separating 30 times.

Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas.

The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 (1) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants. Structure-activity relationship (SAR) exploration at both enzymatic and cellular levels led to the discovery of inhibitor 29. In the biochemical assay, 29 inhibited EZH2 (IC50 = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC50 = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC50 > 30 µM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.

Characterization of the metabolite of cabozantinib generated from liver microsomes and hepatocytes by ultra-high performance liquid chromatography coupled to quadrupole/orbitrap high resolution mass spectrometry.

Cabozantinib is a potent inhibitor of tyrosine kinase receptor that plays key role in tumor pathogenesis. Cabozantinib has been approved by U. S. Food and Drug Administration for the treatment of cancer. The present work was aimed to explore the in vitro metabolism of cabozantinib using liver microsomes and hepatocytes from animal species and humans through ultra-high performance liquid chromatography coupled to quadrupole/orbitrap high resolution mass spectrometer. The metabolites were characterized by their elemental compositions, MS and MS/MS spectra. As a result, a total of 26 metabolites were identified, and 15 metabolites were newly reported. Among these metabolites, M12 (oxidative defluorination), M19 and M22 (demethylation), M21 (hydroxylation) and M26 (N-oxygenation) were the major metabolites in all species. Our data revealed that cabozantinib was metabolized via the following pathways: oxidative defluorination, hydroxylation, amide hydrolysis, O-dealkylation, N-oxygenation, demethylation and glucuronidation. Human recombinant cytochrome P450 (CYP) enzyme analysis revealed that metabolism of cabozantinib was mainly catalyzed by CYP3A4, while other CYP enzymes played negligible role. The current study provided valuable metabolic data of cabozantinib from different animal species and humans, which would aid in safety and efficacy assessment.

Nanocrystal-loaded liposome for targeted delivery of poorly water-soluble antitumor drugs with high drug loading and stability towards efficient cancer therapy.

Nanocrystals (NCs) enable the delivery of poorly water-soluble drugs with improved dissolution and bioavailability. However, their uncontrolled release and instability make targeted delivery challenging. Herein, a nano-in-nano delivery system composed of a drug nanocrystal core and liposome shell (NC@Lipo) is presented, which merges the advantages of drug nanocrystals (high drug loading) and liposomes (easy surface functionalization and high stability) for targeted delivery of hydrophobic drugs to tumors. CHMFL-ABL-053 (053), a hydrophobic drug candidate discovered by our group, was employed as a model drug to demonstrate the performance of NC@Lipo delivery system. Surface PEGylated (053-NC@PEG-Lipo) and folic acid-functionalized (053-NC@FA-Lipo) formulations were fabricated by wet ball milling combined with probe sonication. 053-NC@Lipo enabled high drug loading (up to 19.51%), considerably better colloidal stability, and longer circulation in vivo than 053-NC. Compared with free 053, 053-NC@PEG-Lipo and 053-NC@FA-Lipo exhibited higher tumor accumulation and considerably better in vivo antitumor efficacy in K562 xenograft mice with tumor growth inhibition rate (TGI) of up to 98%. Additionally, more effective tumor cell targeting in vitro and higher TGI in vivo were achieved with 053-NC@FA-Lipo. The NC@Lipo strategy may contribute to the targeted delivery of poorly water-soluble drugs with high drug loading, high stability, and tailorable surface, and has potential for the development of more efficient nanocrystal- and liposome-based formulations for commercial and clinical applications. It may also provide new opportunities for potential clinical application of candidate 053.

Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity.

Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 µM, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 µM, while show weak effect against non-cancerous L02 cell (IC50 > 10 µM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell.

Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML).

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.