Ngokophononongo olupapashwe kwiIseli,abaphandi baye baphuhlisa inhibitor ethile ye-KRASG12C ebizwa ngokuba yi-ARS-1602 ebangele ukuhla kwethumba kwiimpuku.
"Olu phononongo lubonelela ngobungqina bokuba i-KRAS eguqukileyo inokujoliswa ngokukhethiweyo, kwaye ityhila i-ARS-1620 njengemele isizukulwana esitsha se-KRASG12C-specific inhibitors esinamandla onyango," utshilo umbhali okhokelayo, uMatthew R Janes, PhD, ovela kwi-Wellspring Biosciences in. San Diego, CA, kunye nabalingane.
Iinguqu ze-KRAS zezona zidla ngokuguqulwa kwi-oncogene kwaye uphando lwangaphambili lubonise ukuba malunga ne-30% yamathumba aqulethe utshintsho lwe-RAS. Utshintsho oluthile lwe-KRAS lulawula phakathi kweentlobo zethumba. Umzekelo i-KRASG12C lutshintsho oluphambili kumhlaza wemiphunga weseli ongeyonxalenye encinci (NSCLC), kwaye ikwafumaneka kwipancreatic kunye ne-colorectal adenocarcinomas.
Ngaphandle kokuxhaphaka kunye namashumi eminyaka yophando eqaqambisa i-KRAS eguqukileyo njengomqhubi osembindini we-tumorigenesis kunye nokuchasana kweklinikhi, i-KRAS eguqukileyo ibe yithagethi enenkani.
Iintlobo ngeentlobo zezicwangciso zizamile ukuchonga iimolekyuli ezincinci ezijolise kwi-KRAS, kodwa ziye zakhokelela ekucinezeleni okulinganiselweyo kwe-KRAS kwiiseli. Oku kukhuthaze ababhali ukuba bayile i-compound yokuphucula i-KRAS-specific inhibitors, kubandakanywa ne-switch 2 pocket (S-IIP) i-KRASG12C inhibitors ebophelelayo kunye nokusabela kunye ne-GDP-bound state ye-KRAS, ukuyibamba kwi-conformation engasebenziyo.
Ukuze isebenze, i-inhibitor kufuneka ibe namandla aphezulu kunye ne-kinetics yokubopha ngokukhawuleza. Kufuneka kwakhona ibe neepropathi ezifanelekileyo ze-pharmacokinetic zokugcina ukuvezwa kunye nobude bexesha elide elaneleyo lokubamba imeko engasebenziyo ye-GDP ye-KRAS ehamba umjikelo okhawulezayo we-nucleotide.
Abaphandi baqulunqa kwaye badibanisa i-ARS-1620 kunye neempawu ezifana neziyobisi, kunye nokuphucula amandla ngaphezu kweekhompawundi zesizukulwana sokuqala. Ukusebenza kunye ne-kinetics kuyo yonke imigca yeeseli kunye ne-allele eguqukileyo zaye zavavanywa ukuze kuqinisekiswe ukuba indawo ekujoliswe kuyo yokuthintela i-KRAS-GTP kumathumba kwakwanele.
Ukuvinjelwa kokukhula kweeseli, kunye nokuba nokwenzeka kweempendulo ezingezizo ezinokuthi zibonise amandla okuba netyhefu, ziye zavavanywa.
Okokugqibela, ukuvavanya indawo ekujoliswe kuyo kwi-vivo, i-ARS-1620 yomlomo yanikwa iimpuku ezinemifuziselo ye-xenograft esekiweyo ephethe i-KRAS p.G12C njengedosi enye, okanye yonke imihla ngeentsuku ezi-5.
Abaphandi baxela ukuba i-ARS-1620 ithintele kakhulu ukukhula kwethumba kwidosi- kunye nexesha elixhomekeke kwindlela ephawulweyo lokuhlehla kwethumba.
Kwiimodeli ezintlanu ze-xenograft zemigca yeseli ye-NSCLC kwiimpuku, zonke iimodeli ziphendule emva kweeveki ezimbini ukuya kwezintathu zonyango, kwaye ezine kwezintlanu zibonise ukucinezelwa okubalulekileyo kokukhula kwethumba. Ukongeza, i-ARS-1620 yanyanyezelwa kakuhle kwaye akukho tyhefu yeklinikhi ephawulweyo ngexesha lonyango.
"Ngokuhlangeneyo, ubungqina be-vivo bokuba i-ARS-1620 isebenza ngokubanzi njenge-arhente enye kuzo zonke iimodeli ze-NSCLC ibonelela ngobungqina bengcamango yokuba inxalenye ebalulekileyo yezigulane ezine-p.G12C KRAS zokuguqulwa kwe-KRAS zinokuzuza kunyango olujoliswe kwi-KRASG12C," batsho ababhali.
Bongeze ukuba i-ARS-1620 yi-KRASG12C ngqo inhibitor encinci ye-molecule enamandla, ekhethiweyo, efumaneka ngomlomo, kwaye inyamezeleke kakuhle.
Ixesha lokuposa: May-22-2018