Yonke into ngeMonomethyl auristatin E (MMAE)

1.Yintoni i-Antineoplastic Agent MMAE?
2.Monomethyl auristatin E Indlela yokuSebenza
3. I-Monomethyl auristatin E Umsebenzi weBilo
4.Monomethyl auristatin E-Antioclonal Antibodies
5.Monomethyl auristatin E uphando
I-6.Monomethyl auristatin E (MMAE) iinkalo zesakhiwo?
7. I-Monomethyl auristatin E uhlolo


I-Monomethyl auristatin E (MMAE) ividiyo ye powder



I.Monomethyl auristatin E (MMAE) powder Abalinganiswa basisiseko:

igama: I-Monomethyl auristatin E (MMAE) ipowder
CAS: 474645-27-7
I-molecular Formula: C39H67N5O7
Isisindo somzimba: 717.97858
Melt Point: 238-240 ° C
Isitoreji sokugcina: Gcina kwisitya sokuqala, phakathi kwe-36 ukuya kwi-46 degrees F
umbala: Powder


1. Yintoni i-Antineoplastic Agent Monomethyl auristatin E (MMAE)?aasraw

Monomethyl auristatin E (MMAE) yintsebenziswano ye-antinoplastic agent, yaziwa nangokuthi yi-Seattle Genetics kunye
I-Monomethyl auristatin F, Inombolo ye-CAS yi-474645-27-7. Ngenxa yobunobuthi bayo, ngokuqhelekileyo udibaniswa nomntu olwa-monoclonal antibody okhokela kumaseli omhlaza. Ngenxa yokuba i-MMAE ibophelwa ngokukhawuleza kwi-antibody kwaye ihloselwe ukukhutshwa kuphela kwiseli yesifo somhlaza, iziphumo ze-plasma ze-MMAE zihlala ziphantsi. Kwi-laboratory yethu, indlela ye-LC-MS / MS yaqulunqwa ngaphambili nge-LLOQ ye-10 pg / mL. Ngethuba usebenzisa le ndlela ukuxhasa uhlalutyo oluchanekileyo lwesampula, ininzi yesampula yeesampuli i-<LLOQ, ebonisa ukuba i-LLOQ yangoku ayinelanga. Apha siphawula "indlela yokunquma intliziyo" ye-2D-LC-MS / MS ngendlela eneenkqubela zokulingana kwe-MMAE kwiplasma yesikhumba kunye ne-1.0-1200 pg / mL.

474645-27-7

Igama: I-Monomethyl auristatin E (MMAE)

Chemical name: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide

Isisindo somzimba: 717.98

Ifomula: C39H67N5O7

CAS: 474645-27-7

I-MMAE I-Solubility: i-DMSO ukuya kwi-20 mM


2. I-Monomethyl auristatin E Mechanism of Actionaasraw

I-Monomethyl auristatin E indlela yokwenza isenzo se-antimitotic e-inhibits isahlulo seseli ngokuthintela i-polymerization ye-tubulin. Le linker ukuya lomzimba monoclonal uzinzile xa ulwelo extracellular, kodwa isisihla yi cathepsin kanye udibaniso singene iseli ithumba, ngaloo ndlela isebenze indlela antimitotic.


3. I-Monomethyl auristatin E Umsebenzi weBiloaasraw

I-Monomethyl auristatin E (i-MMAE, i-vedotin) inamandla kakhulu i-antimitotic ovimbela isahlulo seseli ngokuthintela i-polymerization ye-tubulini. Iintsapho ze-auristatines zifana neempawu zendalo zendalo ye-Dolastatin 10, i-ultrapotent i-cytotoxic microtubule inhibitors ezisetyenziselwa ukwenziwa kwe-payloads kuma-conjugates.

Monomethyl auristatin E okanye MMAE ngokuphindwe 100-1000 eyingozi ngaphezu doxorubicin (Adriamycin / Rubex) kwaye ayikwazi zingasetyenziswa njenge iziyobisi ngokwayo. Noko ke, njengenxalenye udibaniso omzimba-iziyobisi okanye ADC, Monomethyl auristatin E (MMAE, vedotin) sinxulumene lomzimba monoclonal (-MaB) ukuba uyayiqonda ukuba ibinzana njengommakishi ethile iiseli umhlaza kwaye MMAE ukuya, iseli ethile umhlaza ekujoliswe kuzo.

Le linker edibanisa MMAE ukuya lomzimba monoclonal uzinzile xa ulwelo extracellular, kodwa isisihla yi cathepsin xa lomzimba-drug-udibaniso abophe ukuba iseli somhlaza iantigens ekujoliswe bangena iseli ngumhlaza, emva koko i-ADC ukhupha leli MMAE kunye isebenze indlela yokulwa ne-anti-mitotic. Izifo zogonyamelo lwe-Antibody-drug conjugates ziphucula iziphumo ze-antitumor ze-antibodies kunye nokunciphisa iziphumo ezimbi zenkqubo ye-cytotoxic.

I-Raw Monomethyl auristatin E powder (474645-27-7) hplc =98% | I-powder powder


4. I-Monomethyl auristatin E i-Monoclonal Antibodiesaasraw

I-MMAE ivivinywe ngama-antibodies ahlukeneyo (ngokuqhelekileyo ukwenza i-conjugate ye-antibody-conjugate).

ukubeka iprotein ye-CD30 efunyenwe kwiiseli ezinobungozi kwi-celllas enkulu yeli lymphoma kunye ne-Hodgkin's lymphoma:
-Brentuximab (cAC10), iiyunithi ze-3-5 ze-MMAE nge-molecule
ukubeka i-glycoprotein GPNMB efumaneka kwi-melanoma, i-glioma, umdlavuza webele kunye nezinye izicubu:
-Glembatumumab (i-CR011, i-CDX-011), uphando malunga nokonyango lomhlaza webele kunye ne-melanoma
ukubeka i-CD37:
-AGS67E, ukunyanga i-lymphoid malignancy

imizekelo:

  • Sofituzumab vedotin
  • I-Polatuzumab vedotin (RG7596)
  • Enfortumab vedotin
  • Pinatuzumab vedotin
  • Lifastuzumab vedotin
  • Brentuximab vedotin
  • Glembatumumab vedotin
  • Indusatumab vedotin (MLN-0264) kwiimvavanyo zeqendu II


5. I-Monomethyl auristatin E yophandoaasraw

Umhlaza wesifuba isifo esichaphazelekayo esichazwa yimpendulo eyahlukileyo kwiinkampani ezijoliswe kuzo kunye ne-chemotherapeutic agents. Amaqhinga e-anti-drug conjugates enye yeendlela ezithembisayo zokunyanga umdlavuza webele. I-Monomethyl auristatin E (i-MMAE) iyona nto inamandla kakhulu ye-microtubule inhibitor kunye nomrhumo oqhelekileyo owenzelwe ukuphuhliswa kwee-antiju-drug conjugates. Injongo yale nto I-Monomethyl auristatin E yophando kwakufuneka uphando ngeempembelelo ze-cytotoxic ze-MMAE kwimigca yesifo somhlaza wesisu. Iziphumo zethu zibonise ukuba i-MMAE inemisebenzi ye-cytotoxic eyenza i-dose nexesha elixhomekeke kumaseli omhlaza wesifuba somntu. Iimpawu zokuziphatha eziphathekayo ziseli zisekela umsebenzi we-cytotoxic we-MMAE. Iziphumo zovavanyo lwe-MTT zibonise ukuba i-MMAE ine-cytotoxicity ebalulekileyo malunga ne-MDA-MB-468 kwaye, kwinqanaba elincinci, i-MDA-MB-453 iiseli.

Umdlavuza wesifuba ngowona wesifo esivame ukuxilongwa kunye neyona nto ibangela ukufa kwabantu abachaphazeleka ngumhlaza kwihlabathi jikelele1, kubalwa ukuxilongwa kwe-1 yezigidi kunye nokufa kwabakwa-400,000 ngonyaka. Izidakamizwa ezininzi ze-chemotherapeutic ziye zavunywa ukuba zonyango lomhlaza wesifuba, kodwa unyango olusebenzayo aluhlali lukhulu.

I-Monomethyl auristatin E (i-MMAE), i-auristatin enamandla kakhulu, ihlala isicatshulwa kwizifundo ze-ADC. I-MMAE i-agent e-antimitotic evimbela ukwahlula iseli ngokuthintela i-polymerization ye-tubulini, emele kakhulu i-100- kwi-1000 ngokuphindaphindiweyo kunezidakamizwa ze-chemotherapeutic ezifana ne-vinblastine16,17. I
izidakamizwa okwamanje zisetyenziselwa ukuhlawula umvuzo weentlobo ze-ADC, kuquka iBrentuximab vedotin (i-Adcetis®, i-SGN-35), i-ADC evunywe yi-FDA, kunye ne-ADC ezingaphezu kwe-ezine ze-ADC kwizigaba ezahlukeneyo zokuvavanywa kweeklinikhi. Okubaluleke ngakumbi, i-MMAE isetyenziswe ngokubanzi njengentlawulo yokuhlawula i-ADCs kumdlavuza webele, kuquka iGlembatumomab vedotin (CDX-011, isigaba II) kunye ne-SGN-LIV1A (isigaba I) 16. Ukumiselwa kweMMAE
Ubungakanani be-cytotoxic kwimigqa yesifo somhlaza wesisu luyakwandisa amathuba okuphumelela kwe-ADCs kunyango lomhlaza wesisu.
Kwisifundo samanje, safuna ukuphanda umsebenzi we-MMAE kwiintlobo ezimbini zeengqamu zomhlaza zesifuba, i-MDA-MB-468 kunye ne-MDA-MB-453. Iiseli zavezwa kwiindawo ezahlukeneyo ze-MMAE kwaye impendulo yokukhula yayilinganiswa kwindlela yokuxhomekeka kwimiba kunye nexesha. Emva koko, iseli ye-Cytotoxicity yachongwa ngokusetyenziswa kwe-MTT.

I-Monomethyl auristatin E (MMAE) yophando

Iimpembelelo zeMonomethyl auristatin E (MMAE) ngokusasazeka kwe-MDA-MB-468 (A) kunye ne-MDA-MB-453 (B) iiseli emva kwe48- kunye ne-72-yure yonyango nge-Monomethyl auristatin E (MMAE). Iziphumo ezahlukeneyo (i-1, i-10, i-100, ne-1000 ng / ml) ye-MMAE yavavanywa kwiimizila zeseli, kwaye izinga le-cytotoxcity lalilinganiswa kusetyenziswa i-MTT yesilingo emva kwexesha le-48 ne-72-exposition, njengoko kuchaziwe kwi " kunye neendlela ". Idata ibonisa intsingiselo kwaye imirhumo yephutha ibonisa ukuphambuka okuqhelekileyo (SD) kwezilingo ezimbini ezizimeleyo (ns: P> 0.05, *: P ≤ 0.05, **: P ≤ 0.01,
***: P ≤ 0.001, kunye ****: P ≤ 0.0001).

I-Monomethyl auristatin E (MMAE) yophando

Ukuthelekiswa komsebenzi we-cytotoxic we-Monomethyl auristatin E (MMAE) kwi-MDA-MB-468 kunye nemigca yeseli ye-MDA-MB-453. Iipesenti ze-cell cytotoxicity zamaseli e-MDA-MB-468 aphethwe yi-MMAE ziqheleke kwii-MDA-MB-453 iiseli. Emva kokuqhelekileyo, umphumo we-MMAE kumigca yesibini efaniswa.

I-MMAE yintsebenziswano ye-antinoplastic agent, engasetyenziswanga njengeziyobisi ngokwazo ngenxa yobuthi bayo obuyingozi; kunoko, idibanisa kwi-mAb ukwenza ii-ADC. Nangona uphando malunga namashumi eminyaka, i-ADC ifumene ingqalelo ngokuhlaziywa ngokubaluleka kwezinto zobunjineli ezintsha kunye nezobuchwepheshe bokudibanisa kunye nezidakamizwa ezinamandla kakhulu ze-cytotoxic. Iingxube eziqhelekileyo ezisetyenziswayo kwi-ADC ekuphuculweni kweeklinikhi zi-maytansine, calicheamicin, kunye ne-auristatin derivatives.
Kwisifundo samanje, sikhethe i-tubulin inhibitors enamandla kakhulu ye-tubulin MMAE kuba le ngxube ibonakaliswe kakuhle kwaye ifanelekile ukuguqulwa ukuququzelela ukudibanisa kwi-antibody25. Kuza kube yimhla, isiza seMMAE sisebenzise ngokubanzi ukwakha ii-ADC ezahlukeneyo. I-ADC-based ADCs ezisetyenziselwa ukuhlolwa kweekliniki ziquka

IGlembatumumab vedotin (isigaba II) 26 kunye ne-PSMA-ADC (isigaba I) 27. Kungekudala, i-US FDA ivume i-vc- MMAE ene-ADC, i-brentuximab vedotin (Adcetris®), ekwenzeni i-CD30-positive i-Hodgkin lymphoma kunye ne-systemic iplastic-cell cell lymphoma.

I-Monomethyl auristatin E iphethiso yophando: I-MMAE ibonisa imisebenzi enokumelana neengqambela zesifo somhlaza webele, ekugqibeleni inamandla amakhulu ekuphuhliseni i-ADC malunga nomdlavuza webele.


6. I-Monomethyl auristatin E (MMAE)aasraw

Ukuqonda okutsha kwiimpawu zesakhiwo se-cytotoxic auristatins MMAE ngokubambisana kwe-NMR i-spectroscopy kunye ne-quantum chemical modeling.

The i-antinoplastic agent kunye ne-antimitotic I-MMAE ibonakala njenge-moleyutha yokulayisha i-cytotoxic kwi-ADC ezilishumi elinesibhozo eziye zaqhubekela phambili kwizilingo zesikliniki21. Phakathi kwazo yi-ADC i-Brentuximab vedotin esetyenziselwa unyango lweemeko ezibuyiselwayo zeHodgkin's lymphoma kunye ne-cell prophyma24. I-MMAE iqulethwe yi-five peptide residues kwaye kuye kwabikwa ukuba kukho isisombululo njengomxube wezinto ezimbini ezihambelanayo ngenxa yokujikeleza ngokukhawuleza kwinqanaba le-dolaproine-dolaisoleuine. Isakhiwo samakhemikhali se-cis / trans-isomers, ulwazi malunga nama-residu ase-amino acid kunye nokubala okuza kusetyenziswa kwingxoxo isishwankathelwe kumfanekiso ongezantsi:

Isakhiwo seMonomethyl auristatin E (MMAE)

Nangona ukubonakala kweendlela ezimbini zeMMAE ziqatshelwe ngaphambili, iingxelo malunga nokulungelelaniswa phakathi kweempawu ze-NMR ngamnye kwaye i-molecule ayisekhoyo kwincwadi. Le nto yindawo enengqiqo yokuqala umsebenzi wethu wangoku. Ukuze kunikezelwe iimpawu ezithile kwi-NMR ebonakalayo ebonakalayo ye-MMAE, kwakufuneka ukuba kuhlanganiswe iindlela ze-NMR. Kule sifundo, sisebenzise isixhobo se-NMR se-850 MHz kunye nesethi esilandelayo yeendlela ze-NMR ezibonakalayo: 1D1H kunye ne-13C; I-2D COZY (i-spectroscopy yokulungelelanisa), i-2D13C iphindaphindiweyo i-HSQC (i-heteronuclear-quantum coherence, edHSQC,), i-TOCSY (i-spectroscopy yokudibanisa i-1D kunye ne-2D), i-2D HSQC-TOCSY, i-2D HMBC (i-2D ROESY) (ukujikeleza kwesikhokelo senyukliya umphumo we-overhauser effect spectroscopy). Ngenxa yokuncibilika kwe-MMAE enomlinganiselo omncinci sasebenzisa i-methanol engasetyenziswanga njenge-solvent. Xa kuthelekiswa neendlela ezidumileyo ezidityanisiweyo DMSO-d6 kunye neCD2Cl2, bhetele i-methanol ibonisa indawo enomileyo, njengokuba isisombululo se-polar esingenayo inxaxheba kwi-hydrogen bonding. Enyanisweni, uBenedetti et al. kugqiba ukuba iipropati ezichanekileyo ezigcinwe kule klasi yeemveliso zixhomekeke kwi-solvent dependence, kunye nomlinganiselo omkhulu phakathi kweCD2Cl2 kunye neCD3OD. Iindlela eziphambili zokuchonga nokunika imiqondiso kwi-complex1H- kunye ne-13C-NMR spectra ye-1A kunye ne-1B i-HMBC ne-edHSQC ephezulu-Qinisekisa (Jonga iifayile 3 kunye ne-6 kwiNkcukacha ezongezelelweyo). I-COZY, i-TOCSY (i-2D) kunye ne-HSQC-TOCSY zizo zonke izigaba ezisetyenzisiweyo ukuqinisekisa ukuba izabelo zesignali zazinengqiqo kwaye zichanekile. Le ndlela yafunyaniswa yomelele nakwixesha lokunikezelwa kweendawo ezixubileyo.

Ukuze uthole iinkcukacha ezingaphezulu iinkcukacha, nceda uqhagamshelane ne-AASraw


7. I-Monomethyl auristatin E uhloloaasraw

I-Monomethyl auristatin E uhlolo: MMAE, eyaziwa nangokuthi i-Monomethyl auristatin E, yintengiso ye-antineoplastic. Ngenxa yobunetyhefu, ayikwazi ukusetyenziswa njengeziyobisi ngokwazo; Kunoko, idibene nomntu owenzela i-monoclonal anti (UMAB) oyalela kuwo amaseli omhlaza. Amagama angamaZwe angabandakanyeki kwi-MMAE-MAB-conjugates, igama elithi vedotin libhekisela kwi-MMAE kunye nesakhiwo sayo sokudibanisa kwi-antibody. I-MMAE isichengululo se-antimitotic esinamandla esivela kwiipilptidi ezivela kwi-shell ye-sea-less mollusc i-Dolabella iricricyria ebizwa ngokuthi i-dolastatins ebonisa imisebenzi enamandla kwizifundo ezinqamlekileyo, zombini kwi-vitro nakwi-vivo, ngokubhekiselele kwimiba ye-lymphomas, i-leukemia kunye nezicubu ezinamandla. I-MMAE ibonisa ukufika kwexesha le-200 lewayini le-vinblastine, esinye isilwanyana esibangela i-Hodgkin lymphoma kunye nezinye iintlobo zomhlaza.


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