Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) yog qhov feem ntau hloov pauv subtype ntawm RAS tsev neeg, thiab tau raug suav hais tias yog lub hom phiaj "tsis tsim nyog". Nyob rau hauv xyoo tas los no, covalent mutation inhibitors tsom rau KRASG12C kev hloov pauv tau ua rau muaj kev cuam tshuam loj heev, thiab ob lub molecule inhibitors, AMG510 (Sotorasib) thiab MRTX849 (Adagrasib), tau txais kev pom zoo los ntawm US FDA, uas tau teeb tsa lub nthwv dej ntawm kev tshawb fawb. tshuaj tsom rau lub hom phiaj nyuaj-rau-tshuaj KRAS. Txawm li cas los xij, tseem tsis muaj tshuaj nyob rau hauv kev ua lag luam rau kev hloov pauv uas tsis yog KRASG12C, tshwj xeeb tshaj yog KRASG12D, uas tau pom dav hauv ntau cov qog, thiab tsis ntev los no, Mirati's MRTX1133, raws li thawj qhov ncauj rov qab KRASG12D inhibitor, nyuam qhuav nkag mus rau theem I, uas tau zoo heev. txhawb kev tshawb fawb ntawm cov tshuaj tsom rau qhov kev hloov pauv no.
Tsis ntev los no, pab pawg tshawb fawb ntawm Zhang Ao los ntawm Tsev Kawm Ntawv Pharmacy, Shanghai Jiaotong University thiab pab pawg tshawb fawb ntawm Pang Xiu-feng los ntawm Lub Tsev Kawm Ntawv ntawm Lub Neej, East China Normal University tau koom tes ua ke los ua kom muaj kev vam meej hauv kev tshawb fawb txog kev tiv thaiv qog me me. inhibitors tsom rau KRASG12D kev hloov pauv. Txoj haujlwm tam sim no tau tshaj tawm hauv online hauv thoob ntiaj teb kev lees paub phau ntawv xov xwm Journal of Medicinal Chemistry: https://doi.org/10.1021/acs.jmedchem.3c01724.
Nyob rau hauv txoj kev tshawb no, raws li cov qauv siv lead ua ntawm MRTX1133 complex, cov kws tshawb fawb tau ua cov txheej txheem kev ua kom zoo ntawm thaj tsam P voj nyob los ntawm qhov yooj yim azetidinium bridging nplhaib fragment, lub hnab ntim hydrophobic nyob rau sab laug ntawm lub molecule qhov twg lub nplhaib naphthalene cuam tshuam. , thiab thaj av hnyav uas lub nplhaib pyrrolizidine bicyclic cuam tshuam, ntawm ib sab. Tshwj xeeb, qhov deuteration ntawm benzyloxymethylene, lub peev xwm metabolic qhov chaw, tau ua kom muaj kev ruaj ntseg ntawm cov tebchaw, thaum kev qhia ntawm sidodifluoroolefin hloov pauv tau nce qhov tshiab ntawm cov molecules, ua rau cov chav kawm ntawm pyrrolizidine deuterated compounds nrog sidodifluoroolefin hloov 2. thiab 28.
Daim duab 2. Kev tsim tshuaj raws li tus qauv ntawm KRAS tshiabG12Dinhibitors.
Cov tshuaj 22 thiab 28 tau nthuav tawm cov qib nanomolar qis (0.3 - 1.6 nM) kev loj hlob inhibitory kev ua haujlwm tawm tsam cov kab ntawm tes xws li AsPc-1 thiab AGS qhia txog KRASG12D kev hloov pauv, thiab tsis muaj zog tiv thaiv lwm yam. KRASG12S mutant strain A549 nrog rau KRASWT H1299 hlwb, qhia zoo xaiv rau KRASG12D. Tom qab ntawd, cov tebchaw tau pom tias muaj zog heev hauv inhibiting RAF-RAS protein kev sib cuam tshuam ntawm cov qib molecular los ntawm kev tsim cov homogeneous time-resolved fluorescence (HTRF)-based assay (IC{14}}.48 - 1.19 nM). Ntxiv rau hauv tib neeg cov qog nqaij hlav qog noj ntshav AsPc-1 thiab cov kab mob qog nqaij hlav hauv plab AGS, cov tshuaj tshiab tau ua raws thiab cuam tshuam cov phosphorylation ntawm KRAS downstream proteins ERK thiab AKT. Flow cytometric tsom xam kuj tau pom tias feem pua ntawm cov hlwb apoptotic tom qab 24 teev ntawm kev kho mob ntawm cov tshuaj (50 nM) yog kwv yees li ob zaug siab dua li ntawm pawg tswj hwm dawb paug. Hauv AsPC-1 nas xenograft qog nas qauv, cov tshuaj tshiab tau ua tiav 73.4% thiab 71.3% qog loj hlob inhibition (TGI) nyob rau hauv kev tswj hwm intraperitoneal ntawm 20 mg / kg ob zaug ib hnub, raws li, thaum tsis muaj kev hloov pauv loj hauv cov lub cev hnyav ntawm nas. Western-Blot tsom xam ntawm cov qog nqaij hlav tau pom tias cov tshuaj tshiab tau cuam tshuam cov phosphorylation ntawm KRAS downstream proteins ERK thiab AKT hauv vivo. Ua ke, qhov no qhia tau hais tias cov chav kawm ntawm cov tebchaw no muaj kev nyab xeeb zoo thiab kev tiv thaiv qog nqaij hlav nrog lub peev xwm rau kev tshawb fawb ntxiv.
Daim duab 3. Cov teebmeem ntawm cov qog nqaij hlav hauv cov qog xenograft nas qauv hauv vivo.
