DaxibotulinumtoxinA for injection to treat moderate or severe glabellar lines: A randomized, multicenter, Phase III, double-blind, placebo-controlled trial in China.

BACKGROUND: DaxibotulinumtoxinA for injection (DAXI), a novel botulinum toxin type A formulation, is FDA-approved for glabellar lines treatment. Its clinical efficacy has been demonstrated in two Phase III trials (SAKURA 1 and SAKURA 2). OBJECTIVE: To evaluate DAXI efficacy and safety in Chinese adults with moderate/severe glabellar lines. METHODS: In this Phase III, randomized (2:1), double-blind trial, Chinese adults with moderate/severe glabellar lines received 40 U DAXI or placebo into the corrugator muscles bilaterally and the procerus. Glabellar line severity was evaluated by investigators (Investigator Global Assessment-Frown Wrinkle Severity [IGA-FWS] scale) and participants (Patient Frown Wrinkle Severity [PFWS] scale) for ≥24 to 36 weeks. The primary endpoint was the proportion of 2-point composite responders achieving ≥2-point reduction in IGA-FWS and PFWS scores at week 4 post-treatment. RESULTS: Overall, 307 participants received treatment (DAXI, 205; placebo, 102). A significantly greater proportion of participants in the DAXI arm vs the placebo arm achieved a 2-point composite response at week 4: 125 (61.0%) vs 1 (1.0%); difference, 60.0% [95% CI 49.40-66.46]; 2-sided p < 0.0001). At week 4, 94.1% of the DAXI-treated participants achieved an IGA-FWS score 0/1 (none/mild) and 86.3% achieved PFWS 0/1; median time to loss of none/mild on IGA-FWS and PFWS was 23.9 weeks. The benefits of DAXI over placebo through week 24 occurred regardless of the baseline IGA-FWS score, prior botulinum toxin type A (BoNTA) exposure, sex or age. DAXI was well tolerated with no new safety signals. CONCLUSION: DAXI provided durable efficacy and acceptable safety for treating moderate/severe glabellar lines in Chinese participants.

Optimization of process conditions for ionic liquid-based ultrasound-enzyme-assisted extraction of resveratrol from Polygonum Cuspidatum.

This work offered a productive technique for resveratrol extraction from Polygonum Cuspidatum (P. Cuspidatum) using ionic liquids in synergy with ultrasound-enzyme-assisted extraction (UEAE). Firstly, ionic liquids with different carbon chains and anions were evaluated. Subsequently, a comprehensive investigation was carried out to evaluate the effect of seven crucial parameters on the resveratrol yield: pH value, enzyme concentration, extraction temperature, extraction time, ultrasonic power, concentration of ionic liquid (IL concentration) and the liquid-solid ratio. Employing the Plackett-Burman Design (PBD), the critical factors were effectively identified. Building upon this foundation, the process was further optimized through the application of Response Surface Methodology (RSM) and an Artificial Neural Network-Genetic Algorithm (ANN-GA). The following criteria were determined to be the ideal extraction conditions: an enzyme concentration of 2.18%, extraction temperature of 58 °C, a liquid-solid ratio of 29 mL/g, pH value of 5.5, extraction time of 30 min, ultrasonic power of 250 W, and extraction solvent of 0.5 mol/L 1-butyl-3-methylimidazolium bromide. Under these conditions, the resveratrol yield was determined to be 2.90 ± 0.15 mg/g. Comparative analysis revealed that the ANN-GA model provided a better fit to the experimental data of resveratrol yield than the RSM model, suggesting superior predictive capabilities of the ANN-GA approach. The introduction of a novel green solvent system in this experiment not only simplifies the extraction process but also enhances safety and feasibility. This research paves the way for innovative approaches to extracting resveratrol from botanical sources, showcasing its significant potential for a wide range of applications.

Application of ionic liquid ultrasound-assisted extraction (IL-UAE) of lycopene from guava (Psidium guajava L.) by response surface methodology and artificial neural network-genetic algorithm.

Lycopene-rich guava (Psidium guajava L.) exhibits significant economic potential as a functional food ingredient, making it highly valuable for the pharmaceutical and agro-food industries. However, there is a need to enhance the extraction methods of lycopene to fully exploit its beneficial uses. In this study, we evaluated various ionic liquids to identify the most effective one for extracting lycopene from guava. Among thirteen ionic liquids with varying carbon chains or anions, 1-butyl-3-methylimidazolium chloride demonstrated the highest productivity. Subsequently, a single-factor experiment was employed to test the impact of several parameters on the efficiency of lycopene extraction using this selected ionic liquid. These parameters included extraction time, ultrasonic power, liquid-solid ratio, concentration of the ionic liquid, as well as material particle size. Moreover, models of artificial neural networks using genetic algorithms (ANN-GA) and response surface methodology (RSM) were employed to comprehensively assess the first four key parameters. The optimized conditions for ionic liquid ultrasound-assisted extraction (IL-UAE) were determined as follows: 33 min of extraction time, 225 W of ultrasonic power, 22 mL/g of liquid-solid ratio, 3.0 mol/L of IL concentration, and extraction cycles of three. Under these conditions, lycopene production reached an impressive yield of 9.35 ± 0.36 mg/g while offering advantages such as high efficiency, time savings, preservation benefits, and most importantly environmental friendliness.

Sequential transplantation of exosomes and BMSCs pretreated with hypoxia efficiently facilitates perforator skin flap survival area in rats.

Bone marrow mesenchymal stem cells (BMSC) are promising candidates for the treatment of trans-territory perforator flap necrosis. However, the low retention and survival rate of engrafted BMSCs limit their therapeutic efficacy. Strategies either modifying BMSCs or alleviating the inflammatory environment may solve this problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and hypoxia pretreated BMSCs on flap necrosis. After the perforator flap model was created, the exosomes derived from BMSCs were injected immediately into choke zone II followed by transplantation of hypoxia pretreated BMSCs on Day 2. Gross view was performed to assess the flap survival, enzyme-linked immunosorbent assay was performed to evaluate the inflammatory factor level, microvessel number was assessed and quantitative polymerase chain reaction (qPCR) was performed to assess angiogenesis. We found that exosome delivery significantly reduced inflammatory cytokines levels on Day 1 and Day 3 and promoted the engrafted BMSCs' survival on Day 7. After combining with transplantation of hypoxia pretreated BMSCs, the flap survival rate and the angiogenesis-related gene expression were significantly higher than in the other three groups; the von Willebrand factor (vWF) vascular diameter and vWF vascular count were significantly higher than in the phosphate buffered saline (PBS) group. Thus, we concluded that sequential transplantation of exosomes and BMSCs combinatorially pretreated with hypoxia further facilitated flap survival. This sequential transplantation approach provides novel insights into the clinical treatment of flap necrosis.

Restoring long-lasting midface volume in the Asian face with a hyaluronic acid filler: A randomized controlled multicenter study.

BACKGROUND: Hyaluronic acid (HA) filler treatment is a minimally-invasive alternative to surgery to volumize the cheeks. HAVOL (Restylane® Volyme) is a flexible HA filler suited to contouring and volumizing the midface. METHODS: This randomized, evaluator-blinded, no-treatment controlled study evaluated effectiveness and safety of HAVOL for correction of midface volume deficit and midface contour deficiency in Chinese subjects. In total 111 subjects were randomized to HAVOL and 37 to no treatment (control). The primary endpoint was response, on the blinded evaluator-assessed Medicis Midface Volume Scale (MMVS), at 6 months after last injection for the treatment group and 6 months after randomization for controls, where response was defined as ≥1-point improvement from baseline on both sides of the face. RESULTS: HAVOL was superior to no treatment at 6 months, meeting the primary objective: 76% versus 8% MMVS responders, a difference of 68% (CI: 55.7%-79.4%, p < 0.0001). These effects were sustained in 51% at 12 months after last injection. A majority (≥96%) had improved aesthetic appearance of midface fullness at Month 1 (using the Global Aesthetic Improvement Scale [GAIS]), effects which remained in ≥80% up to 12 months. Volume change captured by 3D photography increased after 1 month to 3.6 mL (close to the total injected volume of 3.4 mL), and remained stable through 12 months. Over 97% reported satisfaction with results after treatment with HAVOL. Additionally, HAVOL was well tolerated, with no unanticipated related adverse events. CONCLUSIONS: This study showed that HAVOL is effective and well tolerated for midface treatment in a Chinese population.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Chin Augmentation and Treatment of Chin Retrusion with a Flexible Hyaluronic Acid Filler in Asian Subjects: A Randomized, Controlled, Evaluator-Blinded Study.

BACKGROUND: Aesthetic improvement of the chin is increasingly requested by patients, including those of Chinese origin. METHODS: A randomized, evaluator-blinded, no-treatment controlled study evaluated the effectiveness and safety of a flexible hyaluronic acid (HA) filler, Restylane® DefyneTM (HADEF), in the correction of chin retrusion in a Chinese adult population over 12 months after treatment. On Day 1, subjects were randomized 3:1 into two groups, HADEF or delayed-treatment controls, and those in the HADEF group were administered treatment. An optional touch-up treatment was administered 1 month after treatment to obtain optimal chin augmentation. The initially untreated control group was offered delayed-treatment after 6 months (including 1-month touch-up). RESULTS: HADEF was superior to no-treatment in improving chin retrusion according to the blinded evaluator at 6 months [Galderma Chin Retrusion Scale (GCRS) responder rate (≥ 1-point improvement from baseline) of 81% vs. 5% for untreated controls; p < 0.001, meeting the primary effectiveness objective. A majority of subjects maintained improvement at 12 months (61% in the HADEF group). All subjects reported satisfaction with results at 6 months after treatment with HADEF and aesthetic improvement rates per the global aesthetic improvement scale (GAIS) were high for 12 months following treatment, with an acceptable safety profile. CONCLUSIONS: These results demonstrated HADEF to be effective and safe for the correction of mild-to-moderate chin retrusion in Chinese subjects, confirming findings previously observed in a western population. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Anticancer effect of covalent purine-containing EGFR TKI, ZZC4 and its mechanism of action through network pharmacology.

AIMS: Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. MAIN METHODS: The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. KEY FINDINGS: The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. SIGNIFICANCE: Our study showed that ZZC4 is an anticancer drug candidate.

Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors.

The EGFRC797S mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFRC797S-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFRDel19/T790M/C797S TK and EGFRL858R/T790M/C797S TK with IC50 values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFRDel19/T790M/C797S) and KC-0122 (BaF3-EGFRL858R/T790M/C797S) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFRC797S-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmRC797S mutation.

Centrifugal Microfluidic Synthesis of Nickel Sesquioxide Nanoparticles.

Nickel sesquioxide (Ni2O3) nanoparticles were synthesized using centrifugal microfluidics in the present study. The obtained nanoparticles were characterized using SEM to investigate their morphology and microstructure, and XRD was employed to analyze their purity. The nanoparticle size data were measured and analyzed using ImageJ (v1.8.0) software. The flow process and mixing procedure were monitored through computational fluid dynamics simulation. Among the synthesized Ni2O3 nanoparticles, those obtained at the rotation speed of 1000 rpm for 10 min with angular acceleration of 4.2 rad/s2 showed the best performance in terms of high purity, complete shape and microstructure, small diameter, and narrow diameter distribution. The experimental results demonstrate that the rotation speed of the microfluidic chip and reaction time contribute to a decrease in particle diameter and a narrower diameter distribution range. In contrast, an increase in acceleration of the rotation speed leads to an expanded nanoparticle size range and, thus, a wider distribution. These findings contribute to a comprehensive understanding of the effects exerted by various factors in centrifugal microfluidics and will provide new insights into nanoparticle synthesis using centrifugal microfluidic technology.

Design, synthesis and evaluation of new pyrimidine derivatives as EGFRC797S tyrosine kinase inhibitors.

The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/T790M/C797S) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed.

Comparison of the efficacy and safety of a 730 nm picosecond titanium sapphire laser and a 755 nm picosecond alexandrite laser for the treatment of freckles in Asian patients: A two-center randomized, split-face, controlled trial.

OBJECTIVE: The 730 nm picosecond titanium sapphire laser is a novel laser that shows promising results in treating freckles. This study aimed to further investigate the efficacy and safety of the 730 nm picosecond titanium sapphire laser for treating freckles in Asian patients compared with those of the 755 nm picosecond alexandrite laser. METHODS: Each face of 86 participants was split into two parts and randomly assigned either one session of 730 or 755 nm picosecond-laser treatment each. Efficacy and safety were determined based on blinded visual evaluations and self-reports at each follow-up visit. RESULTS: The treatment outcomes of the 730 nm picosecond laser for the treatment of freckles were comparable to those of the 755 nm picosecond laser, with 68.99 ± 7.42% and 69.27 ± 7.75% clearance, respectively (p > 0.05). Participants achieved similar Global Aesthetic Improvement Scale scores (4.04 ± 0.31 vs. 4.02 ± 0.30, respectively [p > 0.05]). Additionally, the 730 nm picosecond laser was perceived to be less painful than the 755 nm picosecond laser (4.69 ± 1.63 vs. 5.65 ± 1.80 nm, p < 0.0001). CONCLUSION: The 730 nm picosecond laser is safe and effective for the treatment of freckles in Asian patients. Besides, the 730 nm picosecond laser is less painful than the 755 nm picosecond laser.

Efficacy and Safety of Picosecond Laser in the Treatment of Melasma: A Network Meta-analysis.

BACKGROUND: The role of lasers in the treatment of melasma and acquired hyperpigmentation disease of the skin has been suggested by clinicians. However, there is no consensus on the most efficient and safe treatment method. OBJECTIVE: To systematically evaluate the efficacy and safety of picosecond laser in the treatment of melasma. METHODS AND MATERIALS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese scientific journal database, and Wanfang database were searched. The data for therapeutic efficacy, melasma area and severity score, and incidence rate of adverse reactions were extracted from the included studies. RESULTS: A total of 20 studies involving 1,182 patients were included in this network meta-analysis. Combined therapy with carbamic acid and 1064-nm picosecond laser was the best measure. Melasma area and severity index score of patients after low-power fractional CO2 laser treatment was higher than that of patients after the treatment with 1064-nm picosecond laser. CONCLUSION: Aminomethyl cyclic acid combined with 1064-nm picosecond laser may have the highest effective rate after treatment. Low-power fractional CO2 laser provided the lowest melasma area and severity index score after treatment, and the incidence rate of adverse reactions after treatment, was highest when intense pulsed light was used.

Progress of small molecules for targeted protein degradation: PROTACs and other technologies.

Recent years have witnessed the rapid development of targeted protein degradation (TPD), especially proteolysis targeting chimeras. These degraders have manifested many advantages over small molecule inhibitors. To date, a huge number of degraders have been excavated against over 70 disease-related targets. In particular, degraders against estrogen receptor and androgen receptor have crowded into phase II clinical trial. TPD technologies largely expand the scope of druggable targets, and provide powerful tools for addressing intractable problems that can not be tackled by traditional small molecule inhibitors. In this review, we mainly focus on the structures and biological activities of small molecule degraders as well as the elucidation of mechanisms of emerging TPD technologies. We also propose the challenges that exist in the TPD field at present.

The paired-related homeobox protein 1 promotes cardiac fibrosis via the Twist1-Prrx1-tenascin-C loop.

Cardiac fibrosis is a common pathology in the advanced stage of cardiovascular diseases, which leads to cardiac systolic and diastolic dysfunction. It is important to prevent cardiac fibrosis during myocardial injury. The transcription factor Prrx1 is involved in cancer-associated fibrosis and other organ fibrosis. However, the role and mechanism of Prrx1 in cardiac fibrosis deserves further exploration. We identified that overexpressed Prrx1 promoted the proliferation and migration of cardiac fibroblasts, and transform cardiac fibroblasts to myofibroblasts in vitro. We demonstrated that the expression of Prrx1 is upregulated in TGF-ß1-treated fibroblasts. And silencing Prrx1 could attenuate cardiac fibrosis induced by TGF-ß1 in vitro. In addition, a Twist1-paired-related homeobox 1 (Prrx1)-tenascin-C (TNC) positive feedback loop (PFL) combined with Twist1, Prrx1, and TNC activated fibroblasts, which was the mechanism the Prrx1 in cardiac fibrosis. In conclusion, our findings showed that the deficiency of Prrx1 attenuated cardiac fibrosis in vitro and reveal a novel Twist1-Prrx1-TNC PFL in the regulation of cardiac fibrosis.

Inhibition of intermittent calcium-activated potassium channel (SK4) attenuates Ang II-induced hypertrophy of human-induced stem cell-derived cardiomyocytes via targeting Ras-Raf-MEK1/2-ERK1/2 and CN-NFAT signaling pathways.

Cardiac hypertrophy caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. The intermediate calcium-activated potassium channel (SK4) has been shown to be involved in the process of the inflammatory response, cell proliferation, and apoptosis. However, the role of SK4 in cardiac hypertrophy has not been elucidated. Cardiac hypertrophy in human-induced pluripotent stem cells-derived cardiomyocytes (HiPSC-CMs) was induced by Ang II. Cells were transfected with SK4 adenovirus or treated with SK4 inhibitor (TRAM-34). TUNEL staining was used to assess the levels of apoptosis. Real-time polymerase chain reaction and Western blot analysis were used to measure messenger RNA (mRNA) and protein levels, respectively. The present results showed that SK4 expression was upregulated in HiPSC-CMs stimulated by Ang II. The downregulation of SK4 by a specific inhibitor TRAM-34 markedly ameliorated cardiac hypertrophy (reflected by the mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II treatment. The action of SK4 in cardiac hypertrophy was mediated by Ras-Raf-mitogen-activated protein kinases 1/2 (MEK1/2)-extracellular-regulated protein kinases 1/2 (ERK1/2) and calcineurin (CN)-nuclear factors of activated T cells (NFAT) activation. Our studies demonstrated that inhibition of SK4 significantly alleviated cardiac hypertrophy induced by Ang II in hiPSC-CMs by targeting Ras-Raf-MEK1/2-ERK1/2 signaling and CN-NFAT signaling pathway. Our studies suggest that SK4 may serve as a potential therapeutic target that could delay hypertrophy.

Efficacy and Safety of Polycaprolactone in Treating Nasolabial Folds: A Prospective, Multicenter, and Randomized Controlled Trial.

Nasolabial folds (NLFs) are the most pronounced sign of facial aging. This study explored the efficacy and safety of polycaprolactone gel in treating Chinese patients with moderate-to-severe NLFs. Patients with moderate-to-severe NLF who wished to be treated by dermal fillers were recruited from three centers between July 2017 and September 2019. The randomizing ratio was 1:1 in the polycaprolactone group (polycaprolactone injection) or control group (sodium hyaluronate gel injection). The primary endpoint was the effectiveness rate of Wrinkle Severity Rating Score (WSRS) scores at 12 months after injection. The full-analysis set (FAS) and safety sets had 80 patients in the polycaprolactone group and control group, respectively. In the FAS, the effectiveness rate at 12 months in the polycaprolactone group was 88.8% compared with 23.8% in controls (P < 0.001). The improvement in WSRS sustained during 12 months in the polycaprolactone group, while gradually vanished in the control group since 3 months after surgery. The global aesthetic improvement scale (GAIS) by investigator assessments was improved, much improved, or very much improved in all patients during follow-up, while the proportion of patients with a "no change" assessment gradually increased during follow-up after 6 months in the control group. The rates of injection-related adverse event (AE) and serve injection-related AE were 8.8 versus 11.3% and 0 versus 1.3% in the polycaprolactone group and control groups, respectively. Polycaprolactone gel injection is effective and safe to treat moderate-to-severe NLFs in Chinese patients.

Discovery of Novel, Potent, and Selective Small-Molecule Menin-Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups.

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin-mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin-MLL interaction inhibitors with potent binding affinity and improved physical properties.

Overcoming C797S mutation: The challenges and prospects of the fourth-generation EGFR-TKIs.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have accomplished impressive clinical achievements in the treatment of non-small-cell lung cancer (NSCLC). Nonetheless, the acquired drug resistance largely limits their clinical use. The tertiary C797S mutation in the kinase domain of EGFR is one of the major mechanisms responsible for the drug resistance. Therefore, much attention has been focused on the development of the fourth-generation EGFR-TKIs to target triple mutant epidermal growth factor receptor (EGFR) with C797S mutation. In this review, we outline the panorama of the fourth-generation EGFR-TKIs reported up to now with the attention paid on the design strategy, binding mode and antitumor activity of these EGFR-TKIs. We also discuss the challenges and prospects of the fourth-generation EGFR-TKIs.

Identification of benzamides derivatives of norfloxacin as promising microRNA-21 inhibitors via repressing its transcription.

MicroRNA-21 is a carcinogenic microRNA, whose overexpression arises in a variety of tumor tissues. Hence, microRNA-21 a prospective target for cancer treatment, and regulation of microRNA-21 by small molecule inhibitors is deemed as a promising approach for tumor therapy. In this work, to discover potent microRNA-21 inhibitor, series of 4-(N-norfloxacin-acyl)aminobenzamides were designed and synthesized, and their inhibitory effects were appraised by utilizing dual luciferase reporter assays. The results indicated that compound A7 was the most efficient microRNA-21 small molecule inhibitor. What's more, A7 suppressed the migration of Hela cells and the colony formation of Hela and HCT-116 cells as well as promoted apoptosis of Hela cells. In the mechanism study, results of RT-qPCR certified that A7 could reduce the level of mature microRNA-21 via disrupting its expression at the transcriptional level of its primary form "pri-miR-21", which was distinct from most previous inhibitors directly binding with pre-miR-21. Noticeably, Western blotting and RT-qPCR uncovered A7 could upregulate the expression PTEN, EGR1 and SLIT2, which are the downstream functional targets of microRNA-21. These findings demonstrated that A7 was a promising microRNA-21 small molecule inhibitor and 4-(N-norfloxacin-acyl) aminobenzamide can serve as a new scaffold for discovery of potent microRNA-21 inhibitor.