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Immuno-oncology combinations： raising the tail of the survival curve

Cancer Biology & Medicine 2016年第2期13卷 171-193页

作者： Samuel J. Harris Jessica Brown Juanita Lopez Timothy A. Yap drug development unit Royal Marsden Hospital and The Institute of Cancer Research London SM2 5PT UK Lung unit Royal Marsden Hospital and The Institute of Cancer Research London SM2 5PT UK

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

关键词： Combination drug therapy oncology clinical trials PD-1 PD-L1 CTLA4 biomarkers immunotherapy

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Targeting the PI3K-AKT-mTOR signaling network in cancer

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Chinese Journal of Cancer 2013年第5期32卷 253-265页

作者： Khurum H. Khan Timothy A. Yap Li Yan David Cunningham GI and Lymphoma unit The Royal Marsden NHS Foundation Trust drug development unit The Royal Marsden NHS Foundation Trust Merck & Co. Inc. US Chinese Anti-Cancer Association School of Oncology Peking University Cancer Hospital Beijing Cancer Hospital

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.

关键词：信号网络癌症靶向治疗生物标志物磷酸肌醇细胞生长雷帕霉素哺乳动物

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Current status and trends in small nucleic acid drug development:Leading the future

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Acta Pharmaceutica Sinica B 2024年第9期14卷 3802-3817页

作者： Yuxi Miao Chen Fu Zhaojin Yu Lifeng Yu Yu Tang Minjie Wei Department of Pharmacology School of PharmacyChina Medical UniversityShenyang 110122China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor drug development and Evaluation China Medical UniversityShenyang 110122China Liaoning Medical Diagnosis and Treatment Center Shenyang 110000China Department of Oncology Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyang 110042China

Small nucleic acid drugs,composed of nucleotides,represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based *** agents function by selectively targeting specific genes or their corresponding messenger RNAs(mRNAs),further modulating gene expression and regulating translation-related *** examples within this category include antisense oligonucleotides(ASO),small interfering RNAs(siRNAs),micro-RNAs(miRNAs),and *** emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity,facile design,abbreviated development cycles,expansive target spectrum,and prolonged *** challenges such as poor stability,immunogenicity,and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery *** review provides an overview of the current status and prospective trends in small nucleic acid drug *** with a historical context,we introduce the primary classifications and mechanisms of small nucleic acid ***,we delve into the advantages of the *** and drug Administration(FDA)approved drugs and mainly discuss the challenges encountered during their *** from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues,promoting endosomal escape is a critical scientific question and important research direction in siRNA drug *** directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.

关键词： Small nucleic acid drugs Oligonucleotide drugs siRNA ASO miRNA Aptamer RNAi drug development

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LiBr as an Efficient Catalyst for One-pot Synthesis of Hantzsch 1,4-Dihydropyridines under Mild Conditions

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Chinese Journal of Chemistry 2011年第1期29卷 118-122页

作者： Yadav, D. K. Patel, R. Srivastava, V. P. Watal, G. Yadav, L. D. S. Alternative Therapeutics unit Drug Development Division Medicinal Research Lab Department of Chemistry University of Allahabad Allahabad 211002 India Green Synthesis Lab Department of Chemistry University ofAllahabad Allahabad 211002 India

A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridines has been accomplished via lithium bromide-catalyzed Hantzsch three-component condensation reaction of an aldehyde, α,β-ketoester and ammonium acetate in acetonitrile at room temperature in good to excellent yields. The present protocol is applicable to wide range of substrates including aliphatic, aromatic and heterocyclic aldehydes affording 1,4-dihydropyridines.

关键词： Hantzsch reaction 1,4-dihydropyridines lithium bromide cyclization one-pot procedure multicomponent reactions

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The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1446-1468页

作者： Michael A.Serwetnyk Brian S.J.Blagg Department of Chemistry and Biochemistry Warren Family Research Center for Drug Discovery and DevelopmentUniversity of Notre DameIN 46556USA

The 90-kilo Dalton(kD) heat shock protein(Hsp90) is a ubiquitous,ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein *** many of these clients are overexpressed or become mutated during cancer progression,Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways *** first discovered Hsp90 inhibitors,geldanamycin and radicicol,function by competitively binding to Hsp90’s N-terminal binding site and inhibiting its ATPase ***,most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four ***,alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition,isoform-selective inhibition,and the disruption of Hsp90 protein-protein *** the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex,along with various co-chaperones and immunophilins,the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

关键词： Hsp90 Protein-protein interactions Disruptors Natural products Small molecules Peptidomimetics

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Harnessing generative AI to decode enzyme catalysis and evolution for enhanced engineering

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National Science Review 2023年第12期10卷 13-25页

作者： Wen Jun Xie Arieh Warshel Department of Medicinal Chemistry Center for Natural Products Drug Discovery and DevelopmentGenetics InstituteUniversity of Florida Department of Chemistry University of Southern California

Enzymes, as paramount protein catalysts, occupy a central role in fostering remarkable progress across numerous fields. However, the intricacy of sequence-function relationships continues to obscure our grasp of enzyme behaviors and curtails our capabilities in rational enzyme engineering. Generative artificial intelligence(AI), known for its proficiency in handling intricate data distributions, holds the potential to offer novel perspectives in enzyme research. Generative models could discern elusive patterns within the vast sequence space and uncover new functional enzyme sequences. This review highlights the recent advancements in employing generative AI for enzyme sequence analysis. We delve into the impact of generative AI in predicting mutation effects on enzyme fitness, catalytic activity and stability, rationalizing the laboratory evolution of de novo enzymes, and decoding protein sequence semantics and their application in enzyme engineering. Notably, the prediction of catalytic activity and stability of enzymes using natural protein sequences serves as a vital link, indicating how enzyme catalysis shapes enzyme evolution. Overall,we foresee that the integration of generative AI into enzyme studies will remarkably enhance our knowledge of enzymes and expedite the creation of superior biocatalysts.

关键词： generative AI mutation effects evolution–catalysis relationship enzyme engineering enzyme evolution

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Peptide-drug conjugates(PDCs):a novel trend of research and development on targeted therapy,hype or hope?

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Acta Pharmaceutica Sinica B 2023年第2期13卷 498-516页

作者： Chen Fu Lifeng Yu Yuxi Miao Xinli Liu Zhaojin Yu Minjie Wei Department of Pharmacology School of PharmacyChina Medical UniversityShenyang 110122China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor drug development and Evaluation China Medical UniversityShenyang 110122China Liaoning Medical Diagnosis and Treatment Center Shenyang 110000China Department of Digestive Oncology Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital&InstituteShenyang 110042China

Peptide-drug conjugates(PDCs)are the next generation of targeted therapeutics drug after antibody-drug conjugates(ADCs),with the core benefits of enhanced cellular permeability and improved drug *** drugs are now approved for market by US Food and drug Administration(FDA),and in the last two years,the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer,coronavirus disease 2019(COVID-19),metabolic diseases,and so *** therapeutic benefits of PDCs are significant,but poor stability,low bioactivity,long research and development time,and slow clinical development process as therapeutic agents of PDC,how can we design PDCs more effectively and what is the future direction of PDCs?This review summarises the components and functions of PDCs for therapeutic,from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability,targeting,and stability of the various components of *** holds great promise for the future of PDCs,such as bicyclic peptide-toxin coupling or supramolecular nanostructures for peptide-conjugated *** mode of drug delivery is determined according to the PDC design and current clinical trials are *** way is shown for future PDC development.

关键词： Peptide drug Linker Targeted therapy Stability Permeability

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Role of Moringa oleifera in regulation of diabetes-induced oxidative stress

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Asian Pacific Journal of Tropical Medicine 2013年第6期6卷 426-432页

作者： Dolly Jaiswal Prashant Kumar Rai Shikha Mehta Sanjukta Chatterji Surekha Shukla Devendra Kumar Rai Gaurav Sharma Bechan Sharma Shahidul khair Geeta Watal Alternative Therapeutics unit Drug Development DivisionMedicinal Research Lab.Department of ChemistryUniversity of Allahabad Christopher Bond Life Sciences Center Department of Molecular Microbiology & ImmunologyUniversity of Missouri School of Medicine Department of NMR All India Institude of Medical Sciences Department of Biochemistry.University of Allahabad National Medicinal Plants Boord Alternative Therapeutics unit Drug Development DivisionMedicinal Research Lab.Department of ChemistryUniversity of Allahahad

Objective:To evaluate the antioxidant activity of aqueous extract of Atoringa oleifeta ***) young leaves by in vivo as well as in vitro ***:In vitro study included estimation of total phenolic,total ilavonol,total flavonoid and total antioxidant power(FRAP assay).Tn addition, in vivo study was done with the identified most effective dose of 200 nig/kg of its lyophilized powder on normal and diabetic *** effect on different oxidative free radical scavenging enzymes,viz,superoxide dismutase(SOD),catalase(CAT),glutathione-S-transferase(GST),lipid peroxide(LPO) contents were ***:Significant increase in activities of ***, GST while,a decrease in LPO content was ***,total phenolic,flavonoid and ilavonol contents in the extract were found to be 120 mg/g of CAK,40.5 mg/g of QEK and 12.12 mg/g of QE,*** the other *** assay results of *** leaves was(85.00±5.00)μM of Fe^+/g of extract ***:The significant antioxidant activities of *** leaves from both in vivo as well as in vitro studies suggests that the regular intake of its leaves through diet can protect normal as well as diabetic patients against oxidative damage.

关键词： Moringa oleifera leaves Diabetes Free radical Oxidative damage Scavenging Antioxidant

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A Facile Approach to Fabricate Water-soluble Au-Fe3O4 Nanoparticle for Liver Cancer Cells Imaging

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Chinese Journal of Chemistry 2012年第7期30卷 1387-1392页

作者：梁重时吴献荣谢叶归刘顺英 Shanghai Engineering Research Center for Molecular Theraputics and New drug development East China Normal UniversityShanghai 200062China

Au-Fe3O4 nanoparticles were widely used as nanoplatforms for biologic applications through readily further functionalization. Dopamine （DA）-coated superparamagnetic iron oxide （SPIO） nanoparticles （DA@Fe3O4） have been successfully synthesized using a one-step process by modified coprecipitation method. Then 2--3 nm gold nanoparticles were easily conjugated to DA@Fe3O4 nanoparticles by the electrostatic force between gold nanoparti- cles and amino groups of dopamine to afford water-soluble Au-Fe3O4 hybrid nanoparticles. A detailed investigation by dynamic light scatting （DLS）, transmission electron microscopy （TEM）, fourier transform infrared （FT-IR） and X-ray diffraction （XRD） were performed in order to characterize the physicochemical properties of the hybrid nanoparticles. The hybrid nanoparticles were easily functionalized with a targeted small peptide A54 （AGKGTPSLETTP） and fluorescence probe fluorescein isothiocyanate （FITC） for liver cancer cell BEL-7402 imaging. This simple approach to prepare hybrid nanoparticles provides a facile nanoplatform for muti-functional derivations and may be extended to the immobilization of other metals or bimolecular on SPIO surface.

关键词： dopamine gold superparamagnetic iron oxide hybrid nanoparticles cell imaging

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Two ligands for a GPCR,proton vs lysolipid

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Acta Pharmacologica Sinica 2005年第12期26卷 1435-1441页

作者： Dong-soon IM Laboratory of Pharmacology and Research Institute of drug development College of Pharmacy Pusan National University Busan 609-735 Republic of Korea

Recently,two different chemicals have been matched as ligands with the same G-protein-coupled receptor(GPCR).Double-pairing of OGR 1 family GPCRs with pro-ton and lysolipid raises several ***,whether both are the real ligandsfor the ***,whether modulation ofa GPCR by two chemicals could ***,one of the chemicals is ***-sensing not only is a newaction mode of GPCR activation,but also it could be generalized in other *** this review,I’d like to summarize the issue and discuss questions with pharma-cological criteria.

关键词： lysolipid proton G-protein-coupled receptor sphingosylphosphorylcholine lysophosphatidylcholine psychosine

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