Development of small molecule drugs targeting immune checkpoints

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Research Progress on the Bone Metastasis Mechanism of Prostate Cancer and Bone-Targeted Drugs

Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.

Discussion on gemcitabine combined with targeted drugs in the treatment of pancreatic cancer

Pancreatic cancer is a malignant tumor with poor prognosis.The treatment of pancreatic cancer depends on the tumor stage and type,and includes local treatment(surgery,radiotherapy and ablation intervention)and systemic therapy(chemotherapy,targeted therapy and immunotherapy).We read with great interest the review“Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment”published on World J Gastroenterol and intended to share some of our perspectives in pancreatic cancer treatment.This review presents the therapeutic effects of the combination of gemcitabine and targeted drugs,which gives us a deeper insight into the combination treatments for pancreatic cancer.

Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension

Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related contraindications.With recent advances in precision medicine,precise drug treatment provides better treatment efficacy.Data sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May 2022.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs.According to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and others.All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.Conclusions:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

In silico antiplasmodial effects of phytocompounds derived from Andrographis paniculata on validated drug targets of different stages of Plasmodium falciparum

Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search for new and more potent drugs that target all stages of the Plasmodium falciparum life cycle from natural plant sources.This study aimed to determine the antiplasmodial effect of phytocompounds derived from A.paniculata on the stages of plasmodium falciparum.Methods:Phytocompounds from A.paniculata were identified by Gas Chromatography-Mass Spectrophotometry(GCMS)analysis.The phytocompounds were screened for their druggability using Lipinski’s rule of five and subjected to Absorption,Distribution,Metabolism,Excretion,Toxicity(ADMET)and druglikeness analysis.The phytocompounds were docked against some validated drug targets at different stages of Plasmodium falciparum(hepatic,asexual,sexual,and vector targets)using PyRx software to analyze the inhibitory potential and protein-ligand interaction.Thereafter,the stability and flexibility of the best complexes were assessed through molecular dynamics simulations at 50ns using WebGRO.Result:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl exhibited a higher binding affinity and better stability throughout the simulation period with P.falciparum dihydrofolate reductase-thymidylate synthase and Plasmodium falciparum M1 alanyl aminopeptidase for asexual blood stage and gametocyte stage of Plasmodium falciparum,respectively than the existing drugs.Meanwhile,N-Ethyl-3-methoxy-4-methylphenethylamine was also found to have a higher binding affinity and more stability throughout the simulation period with P.falciparum purine nucleoside phosphorylase and Plasmodium falciparum gametocyte surface protein for Hepatic schizonts stage of Plasmodium falciparum and gametocyte transmission blocking stage,respectively,than the existing drugs.Conclusion:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl and N-Ethyl-3-methoxy-4 methylphenethylamine from A.paniculata are predicted as an antimalarial drug candidate.Thus,it is recommended that in vitro and in vivo bioassays be conducted on these hit compounds to validate these predictions.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Treatment strategies for inflammatory bowel disease(IBD)are rapidly evolving with the development of biologics and small molecule drugs(SMDs).However,these drugs are not guaranteed to be effective in all patients,and a“ceiling effect”of biologic monotherapy may occur.This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses.Thus,the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs.In addition,combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD,which theoretically has multidimensional anti-inflammatory potential.Based on the current evidence available for IBD,dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic treatments or who have extraintestinal manifestation.Additionally,identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission.In this review,we summarize the newly developed biologics and SMDs and the current status of biologics/SMDs to highlight the development of individualized treatment in IBD.

Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment

Pancreatic cancer is highly aggressive and lethal.Due to the lack of effective methods for detecting the disease at an early stage,pancreatic cancer is frequently diagnosed late.Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years,but its anti-tumor effect is limited.Therefore,FOLFIRINOX(leucovorin,fluorouracil,irinotecan,oxaliplatin)as well as combination therapies using gemcitabine and conventional agents,such as cisplatin and capecitabine,has also been administered;however,these have not resulted in complete remission.Therefore,there is a need to develop novel and effective therapies for pancreatic cancer.Recently,some studies have reported that combinations of gemcitabine and targeted drugs have had significant antitumor effects on pancreatic cancer cells.As gemcitabine induced DNA damage response,the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy.Furthermore,KRAS/RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer.Therefore,these characteristics of pancreatic cancer are potential targets for developing effective novel therapies.In this minireview,combinations of gemcitabine and targeted drugs to these characteristics,combinations of targeted drugs,combinations of natural products and anti-cancer agents,including gemcitabine,and combinations among natural products are discussed.

The “predictive molecule targeted chemotherapy” for relapsed ovarian cancer—a pilot study

Objective: How to choose chemotherapy regimen is a often-encountered and formidable problem in the setting of relapsed ovarian cancer. So far, it was usually according to the clinical trials and doctors’ experience and the response rate was very low. In the present study, we proposed a new treatment strategy–the “predictive molecule targeted chemotherapy, PMTC” to choose supposedly sensitive protocols and void supposedly resistant protocols based on the specific predictive molecule expression of individual tumor tissue. Methods: Retrospectively analysis of 16 cases of relapsed ovarian cancer patients from January 2002 to December 2003, as the experience-directed chemotherapy group (control group), to calculate the response rate. Prospectively recruit 9 cases of relapsed ovarian cancer patients after January 2004, whose chemotherapy drug choice was based on the expression of 6 predictive molecules (p53, et al) by means of immunohistochemistry, as the PMTC group, to calculate the response rate. χ2 test was used for the statistical analysis. Results: The response rate of control group was 26%, including 31% for second line and 14% for third line respectively. The response rate of PMTC group was 78%, in which 5 cases of early relapse all responded. The difference was significant (P=0.011). Conclusions: PMTC is a new effective method to treat the relapsed ovarian cancer.

Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.

Role of autophagy in tumorigenesis,metastasis,targeted therapy and drug resistance of hepatocellular carcinoma

Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.

Leishmaniasis:Current status of available drugs and new potential drug targets

The control of Leishmania infection relies primarily on chemotherapy till date.Resistance to pentavalent antimonials,which have been the recommended drugs to treat cutaneous and visceral leishmaniasis,is now widespread in Indian subcontinents.New drug formulations like amphotericin B,its lipid formulations,and miltefosine have shown great efGcacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness.In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite.In context to the limited drug options and unavailability of either preventive or prophylactic candidates,there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease.Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory.This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

Recent advances in lymphatic targeted drug delivery system for tumor metastasis

The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers.

Design and preparation of a new multi-targeted drug delivery system using multifunctional nanoparticles for co-delivery of siRNA and paclitaxel

Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel(PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA) and glucose(Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCopolyethyleneimine(FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu(NPsB) and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.

The Process of How Elderly Patients with Lung Cancer Who Are Receiving Molecularly Targeted Therapy with Oral Agents Establish Self-Management

Purpose: In Japan, many elderly cancer patients are receiving chemotherapy using oral molecularly targeted drugs. They receive treatment in outpatient setting and have a need to self-manage at home. The purpose of this study was to clarify how elderly patients with lung cancer who are undergoing treatment with molecularly targeted drugs in outpatient setting establish self-management. Methods: The study used Kinoshita’s Modified Grounded Theory. Semi-structured interviews were conducted with 17 patients (eight males and nine females). Results: This study identified six categories: Accepting life with cancer, Maintaining activities of daily living without feeling shackled by cancer, Reconsidering how to continue being themselves in daily life until life comes to an end, Using trial and error to integrate treatment and daily living, Formulating their criteria for continuing treatment, and Obtaining help from caregivers. Conclusion: The self-management process in elderly patients consisted of maintaining treatment and integrating treatment with daily living. And they are exploring the effects of treatment and side effects in order to live their own life. Implications for Nursing: In many elderly patients with lung cancer the purpose of treatment is curative extension of survival and improved quality of life. Our findings suggest that is important we help patients to identify how patients want to live, identify ways to improve their quality of life, and share the goals of treatment between the patient and the caregiver.

A Clinical and Animal Experiment Integrated Platform for Small-Molecule Screening Reveals Potential Targets of Bioactive Compounds from a Herbal Prescription Based on the Therapeutic Efficacy of Yinchenhao Tang for Jaundice Syndrome

A herbal prescription in traditional Chinese medicine(TCM)has great complexity,with multiple components and multiple targets,making it extremely challenging to determine its bioactive compounds.Yinchenhao Tang(YCHT)has been extensively used for the treatment of jaundice disease.Although many studies have examined the efficacy and active ingredients of YCHT,there is still a lack of an in-depth systematic analysis of its effective components,mechanisms,and potential targets—especially one based on clinical patients.This study established an innovative strategy for discovering the potential targets and active compounds of YCHT based on an integrated clinical and animal experiment platform.The serum metabolic profiles and constituents of YCHT in vivo were determined by ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry(UPLC-Q-ToF-MS)-based metabolomics combined with a serum pharmacochemistry method.Moreover,a compound–target–pathway network was constructed and analyzed by network pharmacology and ingenuity pathway analysis(IPA).We found that eight active components could modulate five key targets.These key targets were further verified by enzyme-linked immunosorbent assay(ELISA),which indicated that YCHT exerts therapeutic effects by targeting cholesterol 7a-hydroxylase(CYP7A1),multidrug-resistance-associated protein 2(ABCC2),multidrug-resistance-associated protein 3(ABCC3),uridine diphosphate glucuronosyl transferase 1A1(UGT1A1),and farnesoid X receptor(FXR),and by regulating metabolic pathways including primary bile acid biosynthesis,porphyrin and chlorophyll metabolism,and biliary secretion.Eight main effective compounds were discovered and correlated with the key targets and pathways.In this way,we demonstrate that this integrated strategy can be successfully applied for the effective discovery of the active compounds and therapeutic targets of an herbal prescription.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

Network biology:A promising approach for drug target identification against neurodevelopmental disorders

Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions.Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis,prognosis,and treatment.The network of biological entities can help us predict drug targets for several diseases.The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease.The novel strategical approach of system biologyassisted pharmacology coupled with computer-aided drug discovery(CADD)can help drugs fight multifactorial diseases efficiently.In the present review,we have summarized the role and application of network biology for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD,Autism,Epilepsy,and Intellectual Disability.Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of neurodevelopmental disorders.

Drug–Target Interaction Prediction Model Using Optimal Recurrent Neural Network

Drug-target interactions prediction(DTIP)remains an important requirement in thefield of drug discovery and human medicine.The identification of interaction among the drug compound and target protein plays an essential pro-cess in the drug discovery process.It is a lengthier and complex process for pre-dicting the drug target interaction(DTI)utilizing experimental approaches.To resolve these issues,computational intelligence based DTIP techniques were developed to offer an efficient predictive model with low cost.The recently devel-oped deep learning(DL)models can be employed for the design of effective pre-dictive approaches for DTIP.With this motivation,this paper presents a new drug target interaction prediction using optimal recurrent neural network(DTIP-ORNN)technique.The goal of the DTIP-ORNN technique is to predict the DTIs in a semi-supervised way,i.e.,inclusion of both labelled and unlabelled instances.Initially,the DTIP-ORNN technique performs data preparation process and also includes class labelling process,where the target interactions from the database are used to determine thefinal label of the unlabelled instances.Besides,drug-to-drug(D-D)and target-to-target(T-T)interactions are used for the weight initia-tion of the RNN based bidirectional long short term memory(BiLSTM)model which is then utilized to the prediction of DTIs.Since hyperparameters signifi-cantly affect the prediction performance of the BiLSTM technique,the Adam optimizer is used which mainly helps to improve the DTI prediction outcomes.In order to ensure the enhanced predictive outcomes of the DTIP-ORNN techni-que,a series of simulations are implemented on four benchmark datasets.The comparative result analysis shows the promising performance of the DTIP-ORNN method on the recent approaches.