【摘 要】
：
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20％ of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2),which leads to the accumulati
【机 构】
：
Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University,Nanjing 210003,China;Zhuhai
论文部分内容阅读
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20％ of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2),which leads to the accumulation of the carcinogenic metab-olite 2-hydroxyglutarate (2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH 1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140Q acute myeloid leukaemia,SH1573 was effective and safe.
其他文献
Over the past decade,traditional Chinese medicine (TCM) has widely embraced systems biology and its various data integration approaches to promote its modernization.Thus,integrative pharmacology-based traditional Chinese medicine (TCMIP) was proposed as a
IF1 (ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F1Fo-ATP synthase to control ATP production.IF1 activity remains unknown in the regulation of GLP-1 activity.In this study,IF1 was examined in the diet-induced
As one of the most lethal diseases,pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities.Furthermore,pancreatic cancer escapes early detection dur-ing the curable period because early symptoms rarely emerge an
The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous,ATP-dependent molec-ular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates.Because many of these clients are overexpressed or bec
Macrophages are typically identified as classically activated (M1) macrophages and alterna-tively activated (M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these two subtypes plays a critical role i
Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors.How-ever,the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression re-mains elusive.Here we report that LIX1L is over-expressed in human HC
Fusidane-type antibiotics,represented by helvolic acid,fusidic acid and cephalosporin P1,are fungi-derived antimicrobials with little cross-resistance to co mmonly used antibiotics.Generation of new fusidane-type derivatives is therefore of great value,bu
Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role
Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid (BA) re-ceptor TGR5 (also known as Gpbar-1) is a potential drug target
The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogen-esis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases Ⅱ(Pol Ⅱ)an