【摘 要】
：
Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.
【机 构】
：
Department of Medicinal Chemistry and Molecular Pharmacology,Center for Cancer Research,Institute fo
论文部分内容阅读
Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC50)of 2.8 and 0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.
其他文献
Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain.Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain,where the ischemic cascade eventu
ω-Conotoxins inhibit N-type voltage-gated calcium(Cav2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index.Here,we synthesized and characterized a novel ω-conotoxin,Bu8 from Conus bullatus,which consists of 25
Rheumatoid arthritis(RA)is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes(FLS).The up-regulated cellular membrane expres-sion of G protein coupled receptor kinase 2(GRK2)of FLS plays a critical
Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer(NSCLC)is the most frequent malignancy occupying 80％of all lung cancer subtypes.Except for other mutations(e.g.,KRASG1
Many sensitizers have not only photodynamic effects,but also sonodynamic effects.Therefore,the combination of sonodynamic therapy(SDT)and photodynamic therapy(PDT)using sensitizers for sono-photodynamic therapy(SPDT)provides alternative opportunities for
Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regu-lated by molecular motor consisted of myosin and actin cytoskeleton
Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist
Ginsenosides are a series of glycosylated triterpenoids which belong to protopanaxadiol(PPD)-,protopanaxatriol(PPT)-,ocotillol(OCT)-and oleanane(OA)-type saponins known as active compounds of Panax genus.They are accumulated in plant roots,stems,leaves,an
Immunotherapy is a rapidly developing area of cancer treatment due to its higher specificity and potential for greater efficacy than traditional therapies.Immune cell modulation through the admin-istration of drugs,proteins,and cells can enhance antitumor
Blood-brain barrier(BBB)damage after ischemia significantly influences stroke outcome.Com-pound LFHP-1c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains un