Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD

Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

RAS Signaling Targeted Cancer Therapy

Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.

Carbohydrate-based drugs launched during 2000-2021

Carbohydrates are fundamental molecules involved in nearly all aspects of lives,such as being involved in formating the genetic and energy materials,supporting the structure of organisms,constituting invasion and host defense systems,and forming antibiotics secondary metabolites.The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases.During 2000 to 2021,totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents.Here we provide a comprehensive review on the chemical structures,activities,and clinical trial results of these carbohydrate-based drugs,which are categorized by their indications into antiviral drugs,antibacterial/antiparasitic drugs,anticancer drugs,antidiabetics drugs,cardiovascular drugs,nervous system drugs,and other agents.