Ngokocwaningo olushicilelwe kuIseli,abacwaningi benze inhibitor ethile ye-KRASG12C ebizwa nge-ARS-1602 eyenza ukuhlehla kwesimila kumagundane.
"Lolu cwaningo lunikeza ubufakazi obunamandla bokuthi i-KRAS eguquguqukayo ingaqondiswa ngokukhetha, futhi iveza i-ARS-1620 njengemelela isizukulwane esisha se-KRASG12C-specific inhibitors enamandla okwelapha athembisayo," kuphawula umlobi oholayo, u-Matthew R Janes, PhD, waseWespring Biosciences in. San Diego, CA, kanye nozakwabo.
Ukuguqulwa kwe-KRAS kuyi-oncogene evame ukuguqulwa futhi ucwaningo lwangaphambili lubonise ukuthi cishe u-30% wamathumba aqukethe ukuguqulwa kwe-RAS. Ukuguqulwa okuqondile kwe-KRAS kubusa phakathi kwezinhlobo ezithile zesimila. Isibonelo i-KRASG12C iwushintsho olukhulu kumdlavuza wamaphaphu ongewona omncane (i-NSCLC), futhi itholakala ku-pancreatic kanye ne-colorectal adenocarcinomas.
Ngaphandle kokusabalala kanye namashumi eminyaka ocwaningo olugqamisa i-KRAS eguquguqukayo njengomshayeli omaphakathi we-tumorigenesis kanye nokungazweli emtholampilo, i-KRAS eguquguqukayo ibilokhu iyimpoqo enenkani.
Amasu anhlobonhlobo azamile ukuhlonza ama-molecule amancane aqondise i-KRAS, kodwa abangele ukucindezelwa okulinganiselwe kwe-KRAS kumaseli. Lokhu kugqugquzele ababhali ukuthi badizayine inhlanganisela yokuthuthukisa ama-inhibitor aqondene ne-KRAS, okuhlanganisa ne-switch 2 pocket (S-IIP) KRASG12C inhibitors ebophezela futhi isabele ngesimo esibophezeleke ku-GDP se-KRAS, esivalela ekuzihlanganiseni okungasebenzi.
Ukuze isebenze kahle, i-inhibitor kufanele ibe namandla aphezulu kanye ne-kinetics ebopha ngokushesha. Kufanele futhi ibe nezindawo ezisezingeni eliphezulu ze-pharmacokinetic ukuze igcine ukuchayeka kanye nobude besikhathi eside ngokwanele ukuze ibambe isimo sokungasebenzi esiboshwe ku-GDP se-KRAS esibhekana nomjikelezo we-nucleotide osheshayo.
Abaphenyi baklame futhi bahlanganisa i-ARS-1620 ngezakhiwo ezifana nezidakamizwa, kanye namandla athuthukisiwe phezu kwezinhlanganisela zesizukulwane sokuqala. Ukusebenza kahle kanye ne-kinetics kuwo wonke amaseli weseli ane-allele eguquguqukayo bese kwahlolwa ukuze kutholwe ukuthi ingabe ukuhlala okuqondiwe ukuze kuvinjwe i-KRAS-GTP kumathumba kwakwanele.
Ukuvinjelwa kokukhula kwamangqamuzana, kanye nokwenzeka kokusabela okungaqondile okungabonisa amandla okuba nobuthi, kwahlolwa.
Okokugcina, ukuze kuhlolwe ukuhlala okuqondiwe ku-vivo, i-ARS-1620 yomlomo yanikezwa amagundane anamamodeli e-xenograft angaphansi kwesikhumba ane-KRAS p.G12C njengomthamo owodwa, noma nsuku zonke izinsuku ezi-5.
Abaphenyi babike ukuthi i-ARS-1620 ivimbele kakhulu ukukhula kwesimila ngendlela encike kumthamo kanye nesikhathi ngokuhlehla kwesimila.
Kumamodeli amahlanu e-xenograft emigqa yeseli ye-NSCLC kumagundane, wonke amamodeli aphendule ngemva kwamasonto amabili kuya kwamathathu okwelashwa, kanti amane kwayisihlanu abonisa ukucindezela okukhulu kokukhula kwesimila. Ngaphezu kwalokho, i-ARS-1620 yabekezelelwa kahle ngaphandle kokubonwa ubuthi bomtholampilo ngesikhathi sokwelashwa.
"Sekuhlangene, ubufakazi be-in vivo bokuthi i-ARS-1620 isebenza kahle njenge-ejenti eyodwa kuwo wonke amamodeli e-NSCLC bunikeza ubufakazi bomqondo wokuthi ingxenye enkulu yeziguli ezinokuguqulwa kwe-p.G12C KRAS zingazuza ekwelapheni okuqondiswe ku-KRASG12C," kusho ababhali.
Bangeze ngokuthi i-ARS-1620 iyi-KRASG12C inhibitor encane ye-molecule eqondile enamandla, ekhethayo, etholakala ngomlomo, futhi ebekezelelwa kahle.
Isikhathi sokuthumela: May-22-2018