Publications by authors named "Linyu Yang"

13 Publications

  • Page 1 of 1

From natural products to HDAC inhibitors: An overview of drug discovery and design strategy.

Bioorg Med Chem 2021 12 10;52:116510. Epub 2021 Nov 10.

School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. Electronic address:

Histone deacetylases (HDACs) play a key role in the homeostasis of protein acetylation in histones and have recently emerged as a therapeutic target for numerous diseases. The inhibition of HDACs may block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumour cells. Thus, HDAC inhibitors (HDACi) have received increasing attention and many of which are developed from natural sources. In the past few decades, naturally occurring HDACi have been identified to have potent anticancer activities, some of which have demonstrated promising therapeutic effects on haematological malignancies. In this review, we summarized the discovery and modification of HDAC inhibitors from natural sources, novel drug design that uses natural products as parent nuclei, and dual target design strategies that combine HDAC with non-HDAC targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.116510DOI Listing
December 2021

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity.

J Med Chem 2021 10 14;64(20):15379-15401. Epub 2021 Oct 14.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that , as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c01451DOI Listing
October 2021

Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect.

Sci Adv 2021 May 19;7(21). Epub 2021 May 19.

Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.

Microtubules, composed of αβ-tubulin heterodimers, have remained popular anticancer targets for decades. Six known binding sites on tubulin dimers have been identified thus far, with five sites on β-tubulin and only one site on α-tubulin, hinting that compounds binding to α-tubulin are less well characterized. Cevipabulin, a microtubule-active antitumor clinical candidate, is widely accepted as a microtubule-stabilizing agent by binding to the vinblastine site. Our x-ray crystallography study reveals that, in addition to binding to the vinblastine site, cevipabulin also binds to a new site on α-tubulin. We find that cevipabulin at this site pushes the αT5 loop outward, making the nonexchangeable GTP exchangeable, which reduces the stability of tubulin, leading to its destabilization and degradation. Our results confirm the existence of a new agent binding site on α-tubulin and shed light on the development of tubulin degraders as a new generation of antimicrotubule drugs targeting this novel site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abg4168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133757PMC
May 2021

Ion-exchange medium coated with abundant small zwitterions for the purification of soluble proteins.

Prep Biochem Biotechnol 2021 23;51(4):405-413. Epub 2020 Sep 23.

School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.

A new ion-exchange medium was prepared from magnetic particles of ∼1.0 µm through coating with small zwitterions and then functionalizing with ampholytic groups for the isoelectric point of ∼6.4 and denoted MSP-ZEWB. With uricase (MGU) as the model of soluble proteins, the purification of a protein ion-exchange was compared between MSP-ZEWB through elution in discontinuous mode and Toyopearl SP-650C as a classical ion-exchange medium through elution in continuous mode. MGU was adsorbed at pH 7.6 or 8.0 and eluted via competitive displacement by NaCl or electrostatic repulsions with an elution buffer at pH 10 to reverse the type of net charges of MGU. From MSP-ZEWB, MGU was eluted more rapidly with the elution percentages higher than those from Toyopearl SP-650C. For yielding a unit of MGU activity, MSP-ZEWB gave the elution solution volumes that were ∼50% of those obtained with Toyopearl SP-650C. The yields of MGU of the highest purity from MSP-ZEWB were higher than those from Toyopearl SP-650C, but the highest purification folds with both media were comparable. MSP-ZEWB regenerated for 16 times still showed the consistent purification efficacy. Therefore, the ion-exchange media bearing small zwitterion coats showed great promise for the purification of soluble proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10826068.2020.1821218DOI Listing
July 2021

Tranexamic acid reduces blood cost in long-segment spinal fusion surgery: A randomized controlled study protocol.

Medicine (Baltimore) 2020 Sep;99(37):e22069

Department of Orthopedics, The Affiliated Hospital of Southwest Medical University.

Objective: Long-segment spinal fusion surgery was associated with substantial perioperative blood loss which may increase hospitalization expenses and mortality rates. Substantial studies have reported that tranexamic acid (TXA) could reduce blood products and cost after joint arthroplasty surgery. However, there still exists controversy regarding the efficacy of TXA in long-segment spinal fusion surgery. We performed this protocol to design a randomized controlled study to evaluate the efficacy of TXA in decreasing transfusion rate of allogeneic blood products and transfusion cost in degenerative lumbar scoliosis patients.

Methods: This study was carried out as a double-blinded, randomized clinical trial on patients with degenerative lumbar scoliosis who prepared for long-segment spinal fusion surgery from December 2018 to December 2019. It was authorized via the Institutional Review Committee in Southwest Medical University (ky2019225). Eighty patients were divided randomly into 2 groups (Experimental group = 40, control group = 40). The patients in the experimental group received 1000 mg of TXA mixed in 100 mL normal saline as a single dose intravenously over 20 minutes before the skin incision was made. Control group received equivalent normal saline without TXA. Primary outcomes included total blood loss, estimated intraoperative blood loss, hematocrit and hemoglobin decline, postoperative drain amount, intra-/postoperative allogeneic transfusion amount and rate, and total transfusion cost. Secondary outcomes included surgical time, thrombotic complications including deep vein thrombosis and pulmonary embolism. All the needed analyses were implemented through utilizing SPSS for Windows Version 20.0.

Results: Table showed the relevant clinical outcomes between experimental group and control group.

Conclusion: We hypothesized that TXA was effective and safe in reducing blood transfusion and cost in long-segment spinal fusion surgery.

Trial Registration: This study protocol was registered in Research Registry (researchregistry5854).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000022069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489668PMC
September 2020

[Resonance light scattering spectroscopy can directly characterize protein solubility].

Nan Fang Yi Ke Da Xue Xue Bao 2020 Jun;40(6):843-849

Key Laboratory of Medical Laboratory Diagnostics of the Ministry of Education of China, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.

Objective: To develop a fast, sensitive and cost-effective method based on resonance light scattering (RLS) for characterization of protein solubility to facilitate detection of changes in solubility of mutant proteins.

Methods: We examined the response curve of RLS intensities to the protein concentrations in synchronous scanning mode. The curve intersection points were searched to predict the maximal concentrations of the protein in dispersion state, which defined the solubility of the protein in this given state. Bovine serum albumin (BSA, 0-50 g/L) was used as the model to investigate the influences of pH values (6.5, 7.0, and 7.4) and salt concentrations (0.05, 0.10, 0.15, and 0.20 mol/L) on the determined solubility. The solubility of glutathione S-transferase isoenzymes alpha (GSTA, 0-27.0 g/L) and Mμ (GSTM, 0-20.0 g/L) were estimated for comparison. The RLS-based method was used to determine the solubility of uricase (MGU, 0-0.4 g/L) to provide assistance in improving the solubility of its mutants.

Results: We identified two intersection points in the RLS response curves of the tested proteins, among which the lower one represented an approximation of the maximal concentration (or the solubility of the protein) in single molecular dispersion, and the higher one the saturated concentration of the protein in multiple molecular aggregation. In HEPES buffer, the two intersection points of BSA (isoelectric point 4.6) both increased with the increase of pH (6.5-7.4), and their values were ~1.2 g/L and ~33 g/L at pH 7.4, respectively; the latter concentration approached the solubility of commercial BSA in the same buffer at the same pH. The addition of NaCl reduced the values of the two intersection points, and increasing salt ion concentration decreased the values of the lower intersection points. Further characterizations of GSTA and GSTM showed that the low concentration intersection points of the two proteins were ~0.7 g/L and ~0.8 g/L, and their high concentration intersection points were ~10 g/L and ~11 g/L, respectively, both lower than those of BSA, indicating the feasibility of the direct characterization of protein solubility by RLS. The two concentration intersection points of MGU were 0.24 g/L and 0.30 g/L, respectively, and the low concentration intersection point of its selected mutant was increased by 2 times.

Conclusions: RLS allows direct characterization of the solubility of macromolecular proteins. This method, which is simple and sensitive and needs only a small amount of proteins, has a unique advantage for rapid comparison of solubility of low-abundance protein mutants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12122/j.issn.1673-4254.2020.06.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321276PMC
June 2020

Targeting glutaminase1 and synergizing with clinical drugs achieved more promising antitumor activity on multiple myeloma.

Oncotarget 2019 Oct 15;10(57):5993-6005. Epub 2019 Oct 15.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.

Multiple myeloma (MM) pathogenesis remains incompletely understood and biomarkers predicting treatment response still remain lacking. Here we describe the rational mechanisms of combining targeting glautaminase1 (GLS1) with other chemo-reagents for MM treatment. Gls1 is highly expressed cMYC/KRAS12V-drived plasmacytoma (PCT) cells. Down-regulation of Gls1 with miRNAi in cMYC/KRAS12V-expressing BaF3 cells prevented them from growing independence of interleukin 3 (IL3). By using our cMYC/KRAS12V-transduced adoptive plasmacytoma mouse model, we found that Gls1 is involved in PCT pathogenesis. Down-regulation of Gls1 significantly prolonged the survival of PCT recipients. Knockdown of Gls1 increased the expression of Cdkn1a and Cdkn1b and decreased the expression of some critical oncogenes for cancer cell survival, such as c-Myc, Cdk4, and NfκB, as well as some genes which are essential for MM cell survival, such as Irf4, Prdm1, Csnk1α1, and Rassf5. Combination of Gls1 inhibition with LBH589, Bortezomib, or Lenalidomide significantly impaired tumor growth in a MM xenograft mouse model. Our data strongly suggest that Gls1 plays an important role for MM pathogenesis and that combination of GLS1 inhibitor with other MM therapy agents could benefit to MM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800263PMC
October 2019

Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of -Induced B-Cell Acute Lymphoblastic Leukemia.

Clin Cancer Res 2019 12 22;25(24):7527-7539. Epub 2019 Aug 22.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.

Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph B-cell acute lymphoblastic leukemia (B-ALL).

Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity . BL-2 secondary transplantation Ph B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties . -induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.

Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph leukemia cell lines and primary Ph B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph B-ALL, -induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.

Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph B-ALL, including those who relapse after TKI treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0516DOI Listing
December 2019

Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

J Med Chem 2019 04 15;62(8):4158-4173. Epub 2019 Apr 15.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G/G stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00223DOI Listing
April 2019

[Characterization of Mycobacterium tuberculosis dihydrofolate reductase immobilized on magnetic nanoparticles].

Sheng Wu Gong Cheng Xue Bao 2019 Mar;35(3):513-521

Key Laboratory of Medical Laboratory Diagnostics of the Ministry of Education of China, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.

To explore the immobilization of target proteins for screening libraries of ligand mixtures, magnetic submicron particles (MSP) functionalized with Ni²⁺-NTA and carboxyl were compared for the immobilization of Mycobacterium tuberculosis dihydrofolate reductase (MtDHFR). MtDHFR fused with 6×His was expressed, purified and characterized for kinetics. MtDHFR was immobilized on Ni²⁺-NTA-functionalized MSP directly and carboxyl-functionalized MSP upon activation. The immobilization capacity, residual activity, thermostability and affinities for putative inhibitors were characterized. MtDHFR immobilized on Ni²⁺-NTA-functionalized MSP retained about 32% activity of the free one with the immobilization capacity of (93±12) mg/g of MSP (n=3). Ni²⁺ and EDTA synergistically inhibited MtDHFR activity, while Fe³⁺ had no obvious interference. MtDHFR immobilized on carboxyl-functionalized MSP retained (87±4)% activity of the free one with the immobilization capacity of (8.6±0.6) mg/g MSP (n=3). In 100 mmol/L HEPES (pH 7.0) containing 50 mmol/L KCl, there was no significant loss of the activities of the free and immobilized MtDHFR after storage at 0 °C for 16 h, but nearly 60% and 35% loss of their activities after storage at 25 °C for 16 h, respectively. The inhibition effects of methotrexate on the immobilized and free MtDHFR were consistent (P>0.05). The immobilization of MtDHFR on carboxyl-functionalized MSP was thus favorable for higher retained activity and better thermostability, with promise for rapid screening of its ligand mixtures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.13345/j.cjb.180316DOI Listing
March 2019

Yolk-Shell [email protected] Eggette-like Nanostructure: Application in Lithium-Ion and Sodium-Ion Batteries.

ACS Appl Mater Interfaces 2016 Aug 22;8(30):19438-45. Epub 2016 Jul 22.

School of Materials Science & Engineering (SMSE), Beijing Institute of Technology , Beijing 100876, China.

Yolk-shell carbon encapsulated tin ([email protected]) eggette-like compounds (SCE) have been synthesized by a facile method. The SCE structures consist of tin cores covered by carbon membrane networks with extra voids between the carbon shell and tin cores. The novel nanoarchitectures exhibit high electrochemical performance in both lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). As anodes for LIBs, the SCE electrodes exhibit a specific capacity of ∼850 mA h g(-1) at 0.1 C (100 mA g(-1)) and high rate capability (∼450 mA h g(-1) remains) at high current densities up to 5 C (5000 mA g(-1)). For SIBs, the SCE electrodes show a specific capacity of ∼400 mA h g(-1) at 0.1 C and high rate capacity (∼150 mA h g(-1) remains) at high current densities up to 5 C (5000 mA g(-1)).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.6b04736DOI Listing
August 2016

Self-Assembly of Parallelly Aligned NiO Hierarchical Nanostructures with Ultrathin Nanosheet Subunits for Electrochemical Supercapacitor Applications.

ACS Appl Mater Interfaces 2016 Jan 28;8(1):780-91. Epub 2015 Dec 28.

School of Materials Science and Engineering, Central South University , Changsha 410083, Hunan China.

Parallelly aligned NiO hierarchical nanostructures were fabricated using a templated self-assembly method followed by calcinations, where rationally employed pluronic triblock copolymers (P123) are acting as molecular templates for geometrical manipulation of nanocrystals and short-chain alcohols are acting as cosolvents and cosurfactants. Such aligned nanostructure is constructed orderly with several ultrathin two-dimensional (2D) nanosheet subunits with an exceptionally small thickness of only 3 nm in a high degree of orientation and separation. Moreover, the number of assembled nanosheets in a unit can be tuned by changing the concentration of the involving P123. This is the first time to synthesize highly hierarchically ordered and bilaterally symmetrical nanostructures, distributed in diameter of around 200-300 nm, via self-assembly in the liquid phase without solid substrates. The as-synthesized NiO delivered high capacitances of 418 F/g at the current density of 2 A/g with well cycling stability (still maintained 85% after 2000 cycles) and 333 F/g at 10 A/g in rates performance after 60 cycles. These fine electrochemical performances are supposed to be attributed to the hierarchical structures with high specific surface area (SSA, ∼164.87 m(2)/g) and ordered multilevel mesopores, which facilitate the electrolyte accessibility and provide more active sites for redox reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.5b09997DOI Listing
January 2016

Facile Synthesis of Na0.33V2O5 Nanosheet-Graphene Hybrids as Ultrahigh Performance Cathode Materials for Lithium Ion Batteries.

ACS Appl Mater Interfaces 2015 Aug 3;7(31):17433-40. Epub 2015 Aug 3.

§State Key Laboratory of Information Photonics and Optical Communications, Beijing University of Posts and Telecommunications, Beijing 100876, People's Republic of China.

Na0.33V2O5 nanosheet-graphene hybrids were successfully fabricated for the first time via a two-step route involving a novel hydrothermal method and a freeze-drying technique. Uniform Na0.33V2O5 nanosheets with a thickness of about 30 nm are well-dispersed between graphene layers. The special sandwich-like nanostructures endow the hybrids with high discharge capacity, good cycling stability, and superior rate performance as cathodes for lithium storage. Desirable discharge capacities of 313, 232, 159, and 108 mA·h·g(-1) can be delivered at 0.3, 3, 6, and 9 A·g(-1), respectively. Moreover, the Na0.33V2O5-graphene hybrids can maintain a high discharge capacity of 199 mA·h·g(-1) after 400 cycles even at an extremely high current density of 4.5 A·g(-1), with an average fading rate of 0.03% per cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.5b04827DOI Listing
August 2015
-->