Diabetes mellitus has been globally threatening hundreds of millions of people every recent year,of which less than 50%achieve glycemic treatment goal,although several medications of different mechanisms have already ...
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Diabetes mellitus has been globally threatening hundreds of millions of people every recent year,of which less than 50%achieve glycemic treatment goal,although several medications of different mechanisms have already been ***,novel antidiabetic mechanisms and drugs are urgently to be ***/CRTC2 transcriptional complexes are formed once glucagon stimulates the hepatic cells,subsequently elevating hepatic gluconeogenic gene（G6 pase,Pepck,etc.） expression to keep the blood glucose level from dropping off .In diabetic patients,pathologically excessive activation of this pathway causes hyperglycemia with insulin resistance .Therefore,the inhibition of CREB/CRTC2 interaction is a promising approach to ameliorate hyperglycemia by down-regulation of hepatic *** this work,we have designed,synthesized and evaluated a series of compounds that could disrupt the interaction between CREB and CRTC2 based on the structure of natural product Artepllin C（APC）,among which nine compounds have displayed higher potency than APC(IC ~ 30 μM),excluding the possibility of cellular toxin,phosphorylation of CREB and dephosphorylation of ***,the IC50 values of compound A32,A35,AS5,A57（235 nM,158 nM,402 nM,498 nM,respectively） achieved nanomolar levels,which were 60 to above 100-fold more potent than *** studies showed that compound A57 significantly reduced the transcription of G6 pase,Pepck *** vivo studies revealed that A57 caused much more remarkable reduction of fasting and postprandial blood glucose levels than APC did in db/db mice after the same oral dose of *** at finding a more potent and drug-like compound,further optimization of this novel series compounds is underway.
Acute myeloid leukemia（AML） is one of the most common leukemias in adults and if not treated is rapidly *** internal tandem duplication of FLT3 kinase（FLT3-ITD） as a driving oncogenic mutation has been found in ~ ...
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Acute myeloid leukemia（AML） is one of the most common leukemias in adults and if not treated is rapidly *** internal tandem duplication of FLT3 kinase（FLT3-ITD） as a driving oncogenic mutation has been found in ~ 30%of the AML patients and has been actively pursued as a drug discovery target for ***,we discovered a series of FLT3 kinase inhibitors through structure-guided drug design approach,and studied the mechanism of drug *** high throughput screening method,we discovered a BTK kinase inhibitor Ibrutinib,which also displayed moderate potency against FLT3-ITD positive AML cell *** improve this drug activity against FLT3,we discovered a type Ⅰ FLT3 kinase inhibitor ***,the poor oral PK profile prohibited it from further ***,starting from Ibrutinib,we discovered an orally available FLT3 kinase inhibitor CHMFL-FLT3-122,and had entered phase Ⅰ clinical *** order to overcome drug resistance mutations,we continued to explore the binding mode between Ibrutinib and FLT3,and found a potent type Ⅱ FLT3 kinase inhibitor CHMFL-FLT3-213,which displays high potency against drug resistant *** far,most of the candidates were found to be strong against both wt-FLT3 and ***,wt-FLT3 kinase plays an important role in the proliferation and differentiation of hematopoietic stem and progenitor ***,the highly potent and selective FLT3-ITD inhibitors need to explore the biologic and clinical characteristics of ***,we developed compound CHMFL-FLT3-362 that is extremely potent and highly selective against FLT3-ITD with favorable oral pharmacokinetic features,and displayed a GI50 of 30 nM against BaF3-FLT3-ITD and achieved selectivity over both BaF3-TEL-FLT3（25-fold）.
KIT kinase inhibitors,e.g.,imatinib,could induce drug-acquired mutations such as KIT/T670 I that rendered drug resistance after chronic treatment Through a type II kinase inhibitor design approach we discovered a high...
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KIT kinase inhibitors,e.g.,imatinib,could induce drug-acquired mutations such as KIT/T670 I that rendered drug resistance after chronic treatment Through a type II kinase inhibitor design approach we discovered a highly potent type II KIT/T670 I kinase inhibitor compound CHMFL-KIT-284,which potently inhibited KIT gatekeeper T670 I mutant(IC50 =5.3 nM) but not KIT wt(IC50 = 1478 nM).Compound CHMFL-KIT-284 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1(KIT A560-578,GI50 = 19 nM),GIST-T1/T670 I(KIT/T670 I mut,GI50 = 21 nM) and GIST-SR(KIT/T670 I mut,GI50 = 39 nM).In the cellular context it strongly inhibited KIT mediated signaling pathways and induced *** the BaF3-TEL-KIT-T670 I isogenic cell inoculated xenograft mouse model,CHMFL-KIT-284 exhibited dose dependent tumor growth suppression efficacy and 40 mg/kg dosage provided 98%tumor growth inhibition(TGI) without obvious *** believe compound CHMFL-KIT-284 would be a good pharmacological tool for exploration of the KIT-T670 I mutant mediated pathology in GISTs and currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.
Esophageal cancer（EC） is considered to be the sixth leading death cancer worldwide,and its predominant histological subtype is esophageal squamous cell carcinoma（ESCC） in china,which is associated with highly aggr...
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Esophageal cancer（EC） is considered to be the sixth leading death cancer worldwide,and its predominant histological subtype is esophageal squamous cell carcinoma（ESCC） in china,which is associated with highly aggressive and poor prognosis .Aberrant activated PI3 K/Akt/mTOR signaling pathway occurs through multiple mechanisms and contributes to the tumorigenesis of many human tumors,including ESCC .Recent years,there are numerous antitumor inhibitors targeting on the PI3 K/Akt/mTOR signaling ***294002,as the first-generation specific inhibitor of PI3 K,inhibits the catalytic subunit of PI3 K by competing ATP binding sites and regulates PDK/Akt as well as mTOR pathway .Moreover,Rictor,the core subunit of mTORC2,is shown to be amplified in ESCC patients' tissues and viewed as a risk factor for prognosis in ESCC .The aim of this study is to evaluate the effects of Rictor knockdown on cell sensitivity to LY294002 in ESCC and the possible molecular *** found LY294002 obviously restrained cell proliferation in dose-dependent and time-dependent manners by inhibiting PI3 K/Akt/mTOR/p70 S6 K signaling pathway,whereas triggered mTORC2-medicated phosphorylation of Akt（Ser473）/PRAS40（Thr246） in ECa109 and EC9706 *** knockdown of Rictor by shRNA enhanced the inhibitory effects of LY294002 on cell proliferative,migration and colony formation,as well as promoted its effects on cell cycle arrest and cell apoptosis in ***,stable knockdown of Rictor enhanced the antitumor effects of LY294002 by inhibiting tumor growth and promoting cell apoptosis in *** assay revealed that knockdown of Rictor could attenuate LY294002-induced phosphorylation of Akt（Ser473）/PRAS40（Thr246）.Our results provide rationale that combined inhibition of Rictor/mTORC2 and PI3 K for the treatment of ESCC.
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