
GDC-0068 is a potent, highly selective, orally available, ATP-competitive pan-AKT inhibitor, targeting Akt1, Akt2 and Akt3 with IC50 of 5 nM, 18 nM and 8 nM, respectively. It demonstrates high selectivityover more than 200 screened kinases, with >100 fold selectivity for Akt over PKA [1-4].Akt functions as a central role of the PI3K-Akt-mTOR pathway. It is one of the most frequently activated protein serine/threonine kinases in human malignancies. Inhibiting Akt activity has become an attractive approach for cancer treatment. GDC-0068 blocks the phosphorylation of multiple downstream targets of Akt in human cancer cell lines in a dose-dependent manner. It inhibits cell cycle progression and viability of cancer cell lines, most robustly in cells with activated PI3K-Akt-mTOR pathway driven by PIK3CA , PTEN loss and HER2 amplification. GDC-0068 treatment results in pronounced PD effects in tumor xenograft models including dose dependent suppression of p-PRAS40, P-S6 and P-eIF4G, as well as induction of FOXO nuclear localization. GDC-0086 has exhibited antitumor efficacy in multiple xenograft tumor models. In addition, consistent with the role of Akt in a survival pathway, GDC-0068 also demonstrates enhanced antitumor efficacy when combined with other therapeutic agents. GDC-0068 is currently in Phase 1a and Phase 1b clinical development in cancer patients [1-4].
Technical information:
Chemical Formula: | C24H32ClN5O2 | |
CAS #: | 0 | |
Molecular Weight: | 458 | |
Purity: | > 98% | |
Appearance: | White | |
Chemical Name: | (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one | |
Solubility: | Up to 100 mM in DMSO | |
Synonyms: | GDC-0068, GDC0068 |
Shipping Condition: The product is shipped in a glass vial at ambient temperature.Storage condition: For longer shelf life, store solid powder at 4oC desiccated, or store DMSO solution at -20oC.
Reference:
1. | Blake JF, et al. Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors. J Med Chem. 2012. 55(18):8110-27. Pubmed ID:22934575 |
2. | Lin K. GDC-0068: A novel, selective, ATP-competitive inhibitor of Akt. Cancer Res, 2011, 71(8 Supplement), abstract DDT02-01. |
3. | Blake JF. Discovery of GDC-0068: A Selective ATP-competitive Akt Inhibitor for the Treatment of Human Tumors. CHI Next Generation Kinase Inhibitors. June 6-8, 2011. http://www.arraybiopharma.com/_documents/Publication/PubAttachment478.pdf |
4. | Abernero J, et al. Targeting the PI3K-Akt-mTOR pathway with GDC-0068, a novel selective ATP competitive Akt inhibitor. http://www.arraybiopharma.com/_documents/Publication/PubAttachment437.pdf |
Other Information:
Product Specification (pdf) MSDS (pdf) Certificate of Analysis is available upon request.
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RMgX + RX = R-R + MgX2.
这个反应需要的能量比生成格氏试剂的高,
因此降低反应温度是第一个选择。
其次, 增加镁得摩尔比, 让 RX与镁有更多机会反应, 而不是与RMgX。
第三, 降低RX的浓度, 即用更多的溶剂, 因为溶剂和格氏试剂有很显著的溶剂络合。
第四, 缓慢滴加RX., 即降低RX.在反应体系的浓度。
第五, 增加搅拌速率, 即, 让RX.与镁有更好的接触。
认领翻译的战友请跟帖注明“认领本文翻译,48小时内未完成,请其他站友认领”
MaggotsFasterThanScalpelinWoundDebridement
December19,2011—Maggotdebridementtherapy(MDT)appearstobemoreeffectiveforwounddebridementcomparedwithconventionaltherapy,butonlyat1week;afterthattime,anothertypeofdressingshouldbeused,newresearchsuggests.
KristinaOpletalovà,MD,fromtheDepartmentofDermatology,UniversityofCaen,France,andcolleaguespublishedonlineDecember19intheArchivesofDermatology.
MedicalmaggotswereapprovedbytheUSFoodandDrugAdmiNISTrationasamedicaldeviceforwounddebridementin2004.Accordingtotheresearchers,useofmaggotsintreatingwoundsisassociatedwitheffectivewounddebridement,antibacterialeffects,andstimulationofwoundhealing.
However,theypointout,"[r]elativelyfewclinicalstudieshavebeenconductedandtheresultsarenotclear,partlyowingtomethodologicassessmentproblems."
InthecurrentProspective,randomizedcontrolled,phase3clinicaltrial,theresearcherssoughttodeterminetheefficacyofbaggedlarvaeonwounddebridementincomparisonwithconventionaltreatment.
TheprimaryobjectivewastocomparethemeanpercentageofsloughinwoundstreatedwithMDTwiththatofconventionaltreatmentatday15.Thestudyincluded119patientswithanonhealing,sloughywoundthatwas40cm2orsmallerandlessthan2cmdeep.Patientsalsohadananklebrachialindexof0.8orhigher.
Treatmentwasadministeredduringa2-weekhospitalstay.Conventionaltreatmentconsistedofsurgicaldebridement3timesaweekwithascalpel,withuseoftopicalanesthesia.TheMDTwasadministeredusinganencloseddressing(Vitapad,BioMondeLaboratories)containing80sterilemaggots.Atdischarge,aconventionaldressingwasapplied,andpatientswerefollowed-upatday30.
DebridementbyMDTwassignificantlyfasterthansurgicaldebridementduringthefirstweekoftreatment,reachingthesamelevelthecontrolgroupreachedatday15.NobenefitforMDTcomparedwithconventionaltreatmentinhealingrateswasobserved.Atday8,54.5%intheMDTgroupvs66.5%inthecontrolgroup(P=.04)hadevidenceofsloughandwoundhealing.However,byday15,themeanpercentageofsloughwas55.4%intheMDTgroupand53.8%inthecontrolgroup(P=.78).
"AthoughMDTshowsnosignificantbenefitatday15comparedwithconventionaltreatment,debridementbyMDTissignificantlyfasterandoccursduringthefirstweekoftreatment,"theresearchersconclude."Becausethereisnobenefitincontinuingthetreatmentafter1week,anothertypeofdressingshouldbeusedafter2or3applicationsofMDT."
Painscoresweresimilarandmildinbothgroups,althoughincontrasttoconventionaltreatment,MDTwasperformedwithouttopicalanesthesia.
Accordingtotheresearchers,noneofthepatientswerereticentaboutundergoingMDT."[A]crawlingsensationonthewoundwasrarelyandalmostequallynotedinbothgroups,revealingthatthesensationwassubjective,"Dr.Opletalovàandcolleaguespointout.
TwoquestionsregardingMDTremainunanswered,theauthorsnote."Candebridementbeimprovedusingmoremaggotsperdressing?Ifso,wouldthesedressingsbemorepainful?Furtherstudiesareneededtoanswerthesequestions."
ThestudywassupportedbygrantsfromtheClinicalResearchHospitalProgramandfromtheFrenchSocietyofDermatology.Theauthorshavedisclosednorelevantfinancialrelationships.
支原体培养则是取样后在培养基上培养,看有多少支原体菌落会长出,是比较直观和可信的结果。
总体来讲,这两种检查手段可信度都较高,结合一起,不仅可以可靠的知道有无解脲支原体感染,还能知道感染是否严重。

