2 - [[2-Ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] amino] -5,11-dihydro-5,11-dimethyl-6H-pyrimido [4,5-b] [1,4 ] benzodiazepin-6-ib CAS 1234480-50-2

Khoom Piav Qhia

Khoom npe: 2 - [[2-Ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] amino] -5,11-dihydro-5,11-dimethyl-6H-pyrimido [4,5-b] [ 1,4] benzodiazepin-6-ib CAS TSIS: 1234480-50-2

Txhais:

XMD 8-92 (puag dawb);

6H-Pyrimido [4,5-b] [1,4] benzodiazepin-6-ib, 2 - [[2-ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] amino] -5,11-dihydro -5,11-dimethyl-;

Tshuaj& Lub cev nqaij daim tawv

Zog: cov hmoov dawb dawb dawb-dawb

Ntsuas: ≥98.0%

Qhov ceev: 1.3 g / cm3

Lub Ntsiab Kub: 741.8 ℃ ntawm 760 mmHg

Flash Point: 402.4 ℃

Hauv Vitro

XMD8-92 kev nthuav qhia ntau tshaj plaws kev sib raug zoo ntawm BMK1 nrog ntsuas ntsuas kev sib cais tsis tu ncua (Kd) ntawm 80 nM, thaum DCAMKL2, TNK1 thiab PLK4 nthuav tawm Kd's ntawm 190, 890 thiab 600 nM, feem. XMD8-92 muaj kev tiv thaiv zoo rau txhua qhov kev tshawb pom kinases hauv HeLa cell lysates siv cov txuj ci KiNativ thiab pom tias muaj ntau txog 10-ntau dua xaiv rau BMK1 nrog IC50 ntawm 1.5 thanM tshaj qhov tseem ceeb tshaj plaws-cov hom phiaj, TNK1 (IC50=10 μM ) thiab ACK1 (aka TNK2, IC50=18 μM). Lwm qhov tsis muaj zog tawm-lub hom phiaj suav nrog kinase domain 2 ntawm RSK1 thiab RSK2, PIK4A thiab PIK4B, thiab FAK. Qhov tsis zoo, MEK5 tsis tshua muaj zog los ntawm XMD8-92 txog 50 50M [1]. XMD8-92 qhia tau xaiv qhov siab xaiv rau BMK1 hauv kev sib tw hauv vitro ATP-qhov chaw sib tw kom pom kev tiv thaiv 402 kinases zoo li nyob hauv KiNativ tus qauv tawm tsam tag nrho cov kinases nyob hauv HeLa cell lysates. XMD8-92 thaiv EGF-kev ua kom muaj zog ntawm BMK1 nrog IC50 ntawm 240 nM thiab, nrog cov siab li 5 μM, XMD8-92 tsis muaj qhov cuam tshuam rau ERK1 / 2 kev ua haujlwm los ntawm EGF [2].

Hauv Vivo

XMD8-92 cuam tshuam loj hlob ntawm cov qog hlav hauv vivo los ntawm 95%. Cov tshuaj muaj yees ntawm XMD8-92 raug tshuaj xyuas nyob rau hauv Sprague-Dawley nas muab ib leeg ib leeg lossis qhov ncauj noj. XMD8-92 tau pom tias muaj 2.0 hr ib nrab lub neej kev ua haujlwm ntawm 26 mL / min / kg. XMD8-92 muaj cov ntaub so ntswg pes tsawg nrog ib tus xam xam ntawm kev faib tawm ntawm 3.4 L / kg. XMD8-92 muaj qhov ncauj qhov ncauj zoo siab nrog 69% ntawm qhov koob tshuaj nqus. Tom qab ib qho tshuaj qhov ncauj ntawm 2 mg / kg, ntau qhov ntshav plasma ntau ntawm kwv yees li 500 nM tau pom los ntawm 30 feeb, nrog 34 nM tshuav 8 teev tom qab koob tshuaj. Hauv kev sim tshuaj tiv thaiv kev ua siab ntev, ntshav siab ntshav tshuaj ntau ntau (kwv yees li 10 μM tom qab IP koob tshuaj 50 mg / kg) raug tswj thoob plaws 14 hnub. XMD8-92 pom zoo kom ua siab ntev thiab cov nas tau noj qab nyob zoo tsis muaj kev cuam tshuam dab tsi ntawm kev ntxhov siab. Tsis muaj vasculature instability yog pom nyob hauv XMD8-92-kho cov nas [1]. XMD8-92 kev kho mob hauv ob qho tshuaj tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob hauv cov nas tuaj tiv thaiv kev loj hlob ntawm lub ntsws thiab ncauj tsev menyuam xenograft hlav, ntsig txog 95%. Cov txiaj ntsig zoo tiv thaiv qog ntawm XMD8-92 nyob rau hauv lub ntsws thiab ncauj tsev menyuam xenograft qog ua qauv yog vim XMD8-92 lub peev xwm los tiv thaiv qog cell proliferation los ntawm PML kev txwv-pev p21 kuaj cov protein, thiab los ntawm kev thaiv ntawm BMK1 txoj kev koom tes hauv cov qog mob-angiogenesis. Cov. Dhau li, BMK1 knockout (KO) hauv cov nas ua rau kev ua tiav thiab tsis tuaj yeem tshem tawm ntawm BMK1 protein, thaum XMD8-92 kev kho mob hauv cov nas tsuas yog suppresses kev ua haujlwm ntawm BMK1, uas yog thim rov qab. Thib ob, kev tsis txaus ntseeg vasculature pom hauv BMK1 KO nas yuav yog vim tsis muaj C-davhlau ya nyob twg tsis muaj kinase ntawm BMK1, uas tseem muaj nyob rau thaum XMD8-92 kev kho mob ntawm cov tsiaj [2].

Kinase Assay

KiNativ profiling ntawm XMD8-92 yog nqa nrog ob qho ATP thiab ADP acylphosphate-desthiobiotin nrog cov kev hloov kho hauv qab no. HeLa cell lysates (5 mg / mL tag nrho cov protein) yog tsim kom pom cov XMD8-92 ntawm 50 μM, 10 μM, 2 μM, 0.8 μM, thiab 0 μM rau 15 feeb ua ntej ntxiv ntawm ATP lossis ADP acylphosphate sojntsuam ( 5 μM sojntsuam zaum kawg). Tag nrho cov tshuaj tiv thaiv yog ua hauv theej tawm. Sojntsuam cov txheej txheem sojntsuam li 10 feeb thiab cov tshuaj tiv thaiv nres los ntawm kev ntxiv ntawm urea thiab ua rau MS tsom. Cov piv txwv raug txheeb xyuas los ntawm LC-MS / MS ntawm linear ion cuab qhov loj spectrometer siv lub sijhawm "ntu sau" tsim los sau MS / MS spectra los ntawm txhua cov kinase peptide-kev sojntsuam uas tuaj yeem kuaj hauv HeLa cell lysates. Cov hom phiaj no tau tsim thiab siv tau los ntawm kev soj ntsuam ua ntej ntawm HeLa lysates. Txog li plaub tus yam ntxwv sib cais rau txhua kinase peptide-kev sojntsuam sib xyaw yog siv los rho cov cim rau txhua tus kinase, thiab kev sib piv ntawm cov tshuaj kho kom tswj tau (tsis kho) lysates tso cai rau kev txiav txim siab tseeb ntawm% inhibition ntawm txhua kis. Cov ntawv sau cia piav qhia cov ntsiab lus ntawm no tsom mus rau kev ua kom pom huab hwm coj loj yog nyob rau hauv kev npaj [1].

Tsoom thawj coj tsiaj

Cov nas [1] 5 × 105 HeLa cov hlwb tau rov ua haujlwm hauv DMEM thiab txhaj cov dej mus rau sab xis ntawm 6-lub lis piam-hnub Nod / Scid nas (hnub 0). Hnub thib ob (hnub 1) tom qab kev mob qog rau cov qog, cov nas tuaj nkag rau 2 pawg (6 tus tsiaj, XMD8-92, 1-28 hnub, thiab 18 tsiaj, tswj). XMD8-92 (1-28 hnub) pawg tau kho nrog XMD8-92 ntawm koob tshuaj 50 mg / kg ob zaug ib hnub intraperitoneally. Cov pab pawg tswj tau txais txhua hno txhua hnub ntawm cov cab kuj daws raws li kev tswj. Txog hnub 7, pawg tswj hwm tau faib rau 2 pawg (6 tus tsiaj, XMD8-92, 7-28 hnub, thiab 12 tsiaj, tswj hwm). Thiab nyob rau hnub 14, pawg tswj hwm ntxiv uas tau kho yog 2 pawg (6 tus tsiaj, XMD8-92, 14-28 hnub, thiab 6 tus tsiaj tswj,). Kev kho mob nrog XMD8-92 hauv XMD8-92 (7-28 hnub) thiab XMD8-92 (14-28 hnub) pawg yog pib rau hnub 7 thiab hnub 14, ua ntu zus. Lub qog loj dua yog ntsuas siv lub caliper, thiab lub qog ntim tau txiav txim siab [1].

Chiv keeb:

[1]. Yaj Q, et al. Pharmacological inhibition of BMK1 suppresses hlav loj hlob los ntawm promyelocytic leukemia protein.Cancer Cell. 2010 Sep 14; 18 (3): 258-67.

[2]. Yaj Q, et al. Kev ntsuas lub BMK1 MAP kinase pathway hauv kev kho mob qog noj ntshav. Clin Cancer Res. 2011 Jun 1; 17 (11): 3527-32.

[3]. Umapathy G, li al. Lub kinase ALK txhawb lub kinase ERK5 los txhawb cov lus qhia ntawm oncogene MYCN hauv neuroblastoma. Sci teeb liab. 2014 Oct 28; 7 (349): ra102.

Yog tias koj txaus siab rau peb cov khoom lossis muaj lus nug, thov koj xav tiv tauj peb!

Cov khoom lag luam hauv qab patent yog muab rau R& D lub hom phiaj nkaus xwb. Txawm li cas los xij, lub luag haujlwm kawg tau txiav txim siab nrog cov neeg yuav khoom.

Cim npe nrov: 2 - [[2-ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] amino] -5,11-dihydro-5,11-dimethyl-6h-pyrimido [4,5-b] [1,4 ] benzodiazepin-6-ib cas 1234480-50-2, tuam ntxhab, lwm tus neeg, Hoobkas, yuav, hauv Tshuag

• Tug: 2- [2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1-carbonyl] anilino] -5,11-dimethylpyrimido [4,5-b] [1,4] benzodiazepin-6 -one CAS 1234480-84-2
• Tom ntej: Sitaxsentan Sodium CAS 210421-74-2