Raws li peb txhua tus paub, kev txhim kho tshuaj yog qhov ntev, siab - nqis peev, thiab siab - cov txheej txheem pheej hmoo. Ua ntej cov tshuaj tshiab nkag mus rau kev sim tshuaj, hauv - qhov tob thiab kev tshawb fawb hauv lub sijhawm tsis yog- kho mob theem yog qhov tseem ceeb. Preclinical pharmacological kev ntsuas kev ua tau zoo yog qhov tseem ceeb ntawm cov txheej txheem no. Nws koom nrog kev kawm txog hom tshuaj, lawv cov txheej txheem ntawm kev ua, kev xaiv, koob tshuaj - teb kev sib raug zoo, cov teebmeem kev kho mob, thiab cov tshuaj tiv thaiv tsis zoo. Cov kev tshawb fawb txog toxicology suav nrog kev toxicity, mob toxicity, ntev - toxicity, thiab tshwj xeeb toxicity tests. Kev siv cov tshuaj tsim nyog hauv vitro thiab hauv vivo cov qauv uas muaj kev cuam tshuam cov ntsiab lus ntawm kev siv tshuaj thiab cov yam ntxwv kho mob muab kev ruaj ntseg rau cov tshuaj nkag mus rau hauv kev sim tshuaj.
Hauv kev xaus, preclinical pharmacological kev ua tau zoo suav nrog cov hauv qab no tseem ceeb:
1. Mechanism of Action
Kev nkag siab tias cov tshuaj siv nws li cas tom qab nkag mus rau hauv lub cev yog qhov tseem ceeb. Kev paub txog cov txheej txheem ntawm kev ua haujlwm tso cai rau peb los soj ntsuam qhov ua tau ntawm cov khoom lag luam zoo nkag los ntawm kev tshawb fawb cov ntaub ntawv. Hauv kev ua haujlwm tiag tiag, peb tuaj yeem soj ntsuam cov txheej txheem ntawm kev ua haujlwm los ntawm kev txiav txim siab hauv qab no:
⑴Kev Tshawb Fawb: Puas muaj cov ntaub ntawv txaus ntawm lub tshuab no? Xav txog qhov kom muaj nuj nqis thiab qhov zoo ntawm cov kev tshawb fawb cuam tshuam, tshawb pom lub sijhawm ntawm lub hom phiaj, thiab cov kws tshawb fawb koom nrog.
⑵Cov tshuaj uas twb muaj lawm: Puas yog qhov txheej txheem no tau siv ua tiav hauv kev lag luam tshuaj? Thaum qhov no ua pov thawj nws lub peev xwm rau kev txhim kho tshuaj, nws kuj ua rau muaj kev txhawj xeeb txog kev sib tw yog tias lwm cov khoom lag luam twb nyob hauv khw. Kev sib txawv tseem tuaj yeem muab tus nqi lag luam.
⑶Clinical Stage Competitors: Tshawb xyuas lwm lub tuam txhab nrog tshuaj tsom rau tib lub tswv yim. Theem III kev sim nqa hnyav dua qhov kev sim Phase II vim tias lawv koom nrog cov ntaub ntawv ua tau zoo ntawm tus neeg mob. Tsis tas li ntawd, qhov chaw kho mob uas muaj neeg coob coob yuav qhia tau tias muaj kev sib tw yav tom ntej los ntawm cov txheej txheem zoo sib xws -raws li tshuaj. Tsom ntsoov rau cov ntaub ntawv kho mob tshwj xeeb thiab cov xwm txheej tsis zoo.
2. Muaj zog
Potency hais txog kev ua tau zoo ntawm cov tshuaj. Cov cim qhia muaj xws li IC50, EC50, qog inhibition tus nqi, thiab qhov tsawg kawg nkaus inhibitory concentration (MIC). Cia peb delve rau hauv cov kev qhia siv feem ntau rau kev ntsuas tshuaj tiv thaiv kab mob:
⑴IC50 (Ib nrab-Maximal Inhibitory Concentration): Ntawm qhov concentration no, ib qho tshuaj inhibits lossis tua ib nrab ntawm cov chaw kuaj mob (enzymes, receptors, hlwb, thiab lwm yam). IC50 feem ntau yog siv rau hauv vitro cov lus piav qhia txog kev ua tau zoo.
⑵EC50 (Ib nrab-Qhov Ua Tau Zoo Tshaj Plaws): Qhov kev xav tau no ua tiav 50% ntawm cov txiaj ntsig lom neeg siab tshaj plaws. EC50 tuaj yeem piav qhia ob qho tib si hauv vitro thiab hauv vivo cov ntaub ntawv.
⑶Tumor Inhibition Rate: Feem ntau ntsuas nyob rau hauv cov qauv tsiaj, nws quantifies lub inhibition ntawm qog loj hlob.
Siv cov ntsuas qhov muaj zog no, peb tuaj yeem sib piv qhov ua tau zoo ntawm cov tshuaj hom phiaj. Txawm li cas los xij, kev sib piv ncaj qha tsuas yog siv tau thaum siv tib cov qauv kev sim. Nco ntsoov tias qhov kev xeem tshuaj lom neeg tsis tuaj yeem cuam tshuam cov lus xaus yog tias cov ntaub ntawv los ntawm cov kev tshawb fawb sib txawv tsis sib piv ncaj qha.
3. Dose-Kev Sib Raug Zoo
Feem ntau, cov koob tshuaj ntau dua ua rau muaj txiaj ntsig zoo dua nyob rau hauv qee qhov ntau. Thaum aiming rau tib txoj kev kho mob, txo cov tshuaj noj yog xav tau. Kev ntsuas qhov tsawg kawg nkaus ua tau zoo concentration / koob tshuaj thiab ib nrab - qhov siab tshaj plaws concentration / koob tshuaj pab kwv yees cov tshuaj muaj txiaj ntsig ntau npaum li cas.
4. Kev xaiv
Kev xaiv tshuaj ntsuam xyuas cov tshuaj nyiam rau lub hom phiaj tshwj xeeb tshaj lwm tus. Lub hom phiaj yog kom tsis txhob tawm - lub hom phiaj toxicity raws li lub tshuab. Piv txwv li, Bcl-2 inhibitors zoo li APG-2575 thiab ABT-199 (ua lag luam hauv Asmeskas) ob lub hom phiaj Bcl-2. Txawm hais tias tom kawg muaj lub hauv paus pib, qhov sib txawv tseem tuaj yeem muab qhov zoo rau yav dhau los.
Hauv kev xaus, kev nkag siab txog qhov ua tau zoo ntawm cov tshuaj pharmacological yog qhov tseem ceeb rau kev txhim kho tshuaj zoo. Kev tshawb fawb nruj, pob tshab, thiab ua raws li cov hauv paus ntsiab lus tshawb fawb txhim kho cov kev tshawb fawb preclinical yam tsis muaj kev cuam tshuam txog kev muaj tswv yim.
