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.

Synthesis of Ag3PO4/Ag/g-C3N4 Composite for Enhanced Photocatalytic Degradation of Methyl Orange.

In this study, we have successfully constructed Ag3PO4/Ag/g-C3N4 heterojunctions via the hydrothermal method, which displays a wide photo-absorption range. The higher photocurrent intensity of Ag3PO4/Ag/g-C3N4 indicates that the separation efficiency of the photogenerated electron-hole pairs is higher than that of both Ag3PO4 and Ag/g-C3N4 pure substances. It is confirmed that the efficient separation of photogenerated electron-hole pairs is attributed to the heterojunction of the material. Under visible light irradiation, Ag3PO4/Ag/g-C3N4-1.6 can remove MO (~90%) at a higher rate than Ag3PO4 or Ag/g-C3N4. Its degradation rate is 0.04126 min-1, which is 4.23 and 6.53 times that of Ag/g-C3N4 and Ag3PO4, respectively. After five cycles of testing, the Ag3PO4/Ag/g-C3N4 photocatalyst still maintained high photocatalytic activity. The excellent photocatalysis of Ag3PO4/Ag/g-C3N4-1.6 under ultraviolet-visible light is due to the efficient separation of photogenerated carriers brought about by the construction of the Ag3PO4/Ag/g-C3N4 heterostructure. Additionally, Ag3PO4/Ag/g-C3N4 specimens can be easily recycled with high stability. The effects of hydroxyl and superoxide radicals on the degradation process of organic compounds were studied using electron paramagnetic resonance spectroscopy and radical quenching experiments. Therefore, the Ag3PO4/Ag/g-C3N4 composite can be used as an efficient and recyclable UV-vis spectrum-driven photocatalyst for the purification of organic pollutants.

Magnetic CoFe1.95Y0.05O4-Decorated Ag3PO4 as Superior and Recyclable Photocatalyst for Dye Degradation.

The Ag3PO4/CoFe1.95Y0.05O4 nanocomposite with magnetic properties was simply synthesized by the hydrothermal method. The structure and morphology of the prepared material were characterized, and its photocatalytic activity for degradation of the methylene blue and rhodamine B dyes was also tested. It was revealed that the Ag3PO4 in the nanocomposite exhibited a smaller size and higher efficiency in degrading dyes than the individually synthesized Ag3PO4 when exposed to light. Furthermore, the magnetic properties of CoFe1.95Y0.05O4 enabled the nanocomposite to possess magnetic separation capabilities. The stable crystal structure and effective degradation ability of the nanocomposite were demonstrated through cyclic degradation experiments. It was shown that Ag3PO4/CoFe1.95Y0.05O4-0.2 could deliver the highest activity and stability in degrading the dyes, and 98% of the dyes could be reduced within 30 min. Additionally, the photocatalytic enhancement mechanism and cyclic degradation stability of the magnetic nanocomposites were also proposed.

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.

Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus.

Insulin-producing pancreatic ß cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic ß cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic ß cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

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.

Effects of Supplemental Dexmedetomidine Anesthesia on Intracranial Aneurysm Patients Undergoing Intracranial Interventional Embolization.

BACKGROUND: Intracranial aneurysm (IA) has been identified in approximately 0.4%-3% of the population and associated with 3%-10% mortality. IA is the major factor attributing to spontaneous subarachnoid hemorrhage. We aim to investigate that whether employing dexmedetomidine (DEX), an α2 adrenergic receptor agonist, as a supplementation could impact the outcomes of patients with intracranial interventional embolization. METHODS: Patients were randomly divided into a control group (n = 48 cases) and a DEX (0.6 µg/kg) supplement group (n = 48 cases). Patients' outcomes were evaluated using the Glasgow Outcome Scale. Serum levels of norepinephrine, cortisol, interleukin-6, C-reactive protein, neuron-specific enolase, and S100ß were determined using enzyme-linked immunoassay. The cognitive function of patients was assessed using the Mini-Mental State Exam and Montreal Cognitive Assessment tests. RESULTS: DEX supplementation during anesthesia reduced adverse reaction, surgical stress, and attenuated cognitive impairment after extubation in IA patients' postintracranial interventional embolization. CONCLUSIONS: Our study demonstrated that employing DEX as supplementation during anesthesia could effectively reduce surgical stress and improve cognitive function, ultimately improving patients' recovery from intracranial interventional embolization.

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.

Foam stability of temperature-resistant hydrophobic silica particles in porous media.

The world is rich in heavy oil resources, however, the recovery difficulty and cost are both higher than that of conventional crude oil. To date, the most common method of recovering heavy oil is steam flooding. However, once the steam breaks through the geological formation, gas channeling readily occurs, which leads to a rapid decrease of the steam drive efficiency. To improve the swept volume of steam in the geological formation, a series of hydrophobic silica particles for stabilizing foam was synthesized. This kind of particles used hydrophilic nano silica particles as reactant. Hydrophobic groups with cationic long carbon chains were grafted onto the surface of hydrophilic silica particles by synthetic silane quaternary ammonium salt. When the quantity of silane quaternary ammonium salt used in the modification reaction is different, the product had various degrees of wettability. The hydrophobic particles with the contact angle closest to 90° had the best foam stabilization effect on the betaine zwitterionic surfactant LAB. For LAB solution with mass fraction of 0.3%, the half-life of foam was extended into 160% when the mass fraction of particles was 0.5%. The higher the gas-liquid ratio, the better the plugging effect of foam agent with hydrophobic particles presented in porous media. The adsorption test of hydrophobic particles indicated that hydrophobic particles improved the stability of foam liquid membrane by improving the adsorption capacity of surfactant molecules. The thermal stability of hydrophobic silica particles exceeded 200°C, and the good foam stability made it a potential additive for foam oil displacement in high-temperature geological formation.

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.

Discovery of IHMT-MST1-58 as a Novel, Potent, and Selective MST1 Inhibitor for the Treatment of Type 1/2 Diabetes.

The critical pathogenesis of type 1 diabetes (T1D)/type 2 diabetes (T2D) is the physical status, mass, and function of pancreatic ß cells. Mammalian STE20-like protein 1 kinase (MST1) plays vital roles in the apoptosis and insulin secretion of ß cells. Here, we discovered a novel, potent, and selective MST1 inhibitor 19 (IC50 = 23 nM), which inhibited the phosphorylation of MST1-protected ß 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 ß 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.

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.

Synthesis of a Superhydrophobic Fluorinated Nano-Emulsion and Its Modification on the Wettability of Tight Sandstone.

The water-blocking effect is a serious problem when developing tight sandstone gas reservoirs, which can cause a sharp reduction in gas production. Wettability alteration of near-wellbore sand rock surface from superhydrophilicity to superhydrophobicity is an effective method to decrease capillary pressure. In this study, a superhydrophobic fluorinated nano-emulsion was synthesized via a soap-free emulsion polymerization process using methacryloxyethyl trimethyl ammonium chloride, trifluoctyl methacrylate, and styrene as monomers. The effect of the fluorinated monomer concentration on wettability alteration was evaluated by measuring the contact angle of the formation water droplet on the modified glass slides using nano-emulsions with different fluorinated monomer concentrations. The results showed that the nano-emulsion had a good dispersibility and homogeneous particle size of around 90 nm, and with the increase in fluorinated monomer concentration, the contact angle increased. The contact angle was the largest when the fluorinated monomer mass rate concentration reached 50%. The adsorption of nanoparticles could alter the rock wettability from a super hydrophilic state (θ = 7°) to a superhydrophobic state (θ = 150°). The spontaneous imbibition experiments showed that the formation water adsorption quality of the core decreased by 49.7% after being modified by the nano-emulsion. The nano-emulsion showed a good superhydrophobicity and had the potential to be used to reduce the water-blocking damage in the tight gas reservoirs.

Magnetic Hyperbranched Molecular Materials for Treatment of Oily Sewage Containing Polymer in Oilfield Compound Flooding.

With the continuous improvement in oilfield development and the application of tertiary oil recovery technology, the water content of oilfield-produced fluids has gradually increased, and a large number of oilfield sewage with complex components has also been produced after oil-water separation, and effective treatment is urgently needed. ASP flooding sewage contains alkali, various surfactants, polymers, microemulsion oil droplets, and solid impurities, which are difficult to be effectively treated by traditional water treatment agents and methods. In this study, aminopropyl triethoxysilane (APTES) was used to modify the nano-Fe3O4 coated with tetraethyl silicate (TEOS). The product was used as the ferromagnetic nano-core for the iterative reaction of Michael addition and ester amidation to synthesize a magnetic hyperbranched polyamide amine, and its performance in the treatment of ASP flooding wastewater was evaluated experimentally. For the preparation of APTES-modified Fe3O4@SiO2 (FOSN) product, TEOS was coated over Fe3O4 in an ethanol aqueous solution environment and then APTES was added dropwise. The first-generation branched product (1-FSMN) was obtained by the reaction of FOSN and methyl acrylate graft product (FOSN-M) with ethylenediamine, and the highest yield was 93.7%. The highest yield of the second-generation branched product (2-FSMN) was 91.6%. In this study, a composite flooding wastewater sample from a block in the Bohai oilfield was taken. The suspended solids content was 143 mg/L, the oil content was 921.09 mg/L, the turbidity was 135 NTU, and the zeta potential was -47 mV. The third-generation hyperbranched polymer (3-FSMN) and its quaternary ammonium salt (3-FSMN-Q) performed best in the appropriate dosage range, with the highest oil removal rate of 97%, suspended solid removal rate of 90.3%, turbidity reduction rate of 86.6% and zeta potential reduction rate of 88%. For 3-FSMN and its quaternary ammonium salt, the gravity/magnetic PAC compound treatment experiment was carried out. In the settlement time of only 5 min, 3-FSMN/PAC and 3-FSMN-Q/PAC can achieve the maximum oil removal rate of 87.1% and suspended solids removal rate of 87.3% for polymer containing wastewater from ASP flooding, and 86.3 and 86.0% for 120 mg/L. Its treatment capacity was much better than that of common treatment agent combination (CPAM/PAC).

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.