Cov Kws Tshawb Fawb Tau Tsim Kev Tsim Ib Nub Tuaj Ntawm BCR-ABL Kinase Cov Neeg Nyuaj Sab Nrauv uas Ua Tau Kev Tuav Pov Hwm Imatinib

Liu Qingsong, tus kws tshawb fawb ntawm lub koom haum ntawm Kev Noj Qab Haus Huv thiab Kev Kho Mob thev Naus Laus Zis, Hefei Tshawb Fawb Lub Chaw Haujlwm, Suav Academy ntawm Kev Tshawb Fawb, tau ua qhov kev nce qib tshiab hauv kev kho tus mob myelogenous leukemia (CML) thiab tsim lub cim tshiab ntawm BRC-ABL kinase inhibitor uas tuaj yeem kov yeej ntau txoj kev tsis kam hloov ntawm imatinib CHMFL-48, cov kev tshawb fawb tshawb fawb tau tshaj tawm online nyob rau hauv European Journal of Pharmacology.

Tus mob hu ua myelogenous leukemia yog mob cov pob txha mob hauv lub cev cov ntshav pob txha mos, uas yog kwv yees li 15% ntawm cov neeg mob qog nqaij hlav tshiab rau cov laus. BCR-ABL fusion noob yog qhov tseem ceeb tshaj plaws ua rau CML, yog li nws tau kawm dav dav raws li lub hom phiaj tshuaj. Raws li thawj zaug BCR-ABL inhibitor pom zoo rau kev lag luam, imatinib tau ua tiav siv thawj kab kev kho mob ntawm CML. Txawm li cas los xij, cov kev tshawb fawb pom tau tias nrog lub caij nyoog siv tshuaj kho mob ntev, nws yog kev tsis pom dhau los tias yuav muaj lub sijhawm thib ob vim yog lub hom phiaj hauv chaw kho mob. Yeeb tshuaj tiv thaiv tshwm sim los ntawm kev hloov pauv. Txawm hais tias cov kab mob thib ob xws li dasatinib tuaj yeem kov yeej qee qhov kev hloov pauv, lawv tsis tuaj yeem kov yeej T315I kev hloov pauv hauv BCR-ABL tus neeg zov me nyuam. Txawm hais tias cov tshuaj thib peb cov kab mob panatinib tuaj yeem kov yeej T315I kev hloov pauv, nws muaj feem ua rau muaj kev pheej hmoo ntawm cov leeg txha caj qaum, mob ntshav tawm ntawm lub plawv, thiab muaj kev mob ntshav siab ntau, txwv nws txoj kev kho mob. Yog li no, kev txhim kho ntawm BCR-ABL inhibitor uas tuaj yeem kov yeej ntau yam kev hloov pauv ntawm imatinib thiab muaj kev nyab xeeb zoo muaj cov nqi tseem ceeb hauv chaw kho mob.

Cov kws tshawb nrhiav tau siv khoos phis tawm-siv tshuaj pab thiab tsim cov roj ntsha me me uas tsim los CHMFL-48 los ntawm kev tsim qauv. Cov kev tshawb fawb muaj protein thiab xov tooj ntawm tes tau qhia tias CHMFL-48 tuaj yeem tiv thaiv cov tsiaj qus hom BCR-ABL (wt) kinase thiab cov koob tshuaj tiv thaiv kev tsis sib haum, suav nrog T315I, F317L, E255K, Y253F thiab M351T. Hauv kev kuaj pom ntawm BCR-ABL qus-hom thiab BCR-ABL mutant cell signaling pathways, tau pom tias CHMFL-48 tuaj yeem cuam tshuam cov autophosphorylation ntawm BCR-ABL thiab nws cov dej ntws qis hauv cov cim, xws li STAT5 thiab CRKL; thiab thaiv lub voj voog ntawm tes hauv G0-G1 theem, cell apoptosis yog yuam. Hauv kev sim tshuaj vivo pharmacodynamic qhia tau hais tias CHMFL-48 tuaj yeem tiv thaiv qhov kev loj hlob ntawm cov nas subcutaneous hloov cov qog uas tsim los ntawm K562 hlwb ntawm ib koob ntawm 25 mg / kg / hnub, thiab cov qog tsis ua haujlwm (TGI) tuaj yeem ncav cuag 100%. Tus nas ua qauv tsim los ntawm p210-T315I BaF3 cov hlwb tseem pom tias muaj cov kabmob ua haujlwm zoo. Thaum ib koob tshuaj 100 mg / kg / hnub, qhov qog-inhibition tus nqi tuaj yeem ncav cuag 48%.