Maererano neongororo yakabudiswa munaSero,vatsvakurudzi vakagadzira chaiyo inhibitor yeKRASG12C inonzi ARS-1602 iyo yakakonzera kudzoka kwebundu mumakonzo.
"Chidzidzo ichi chinopa humbowo hwekuti mutant KRAS inogona kutariswa zvakasarudzwa, uye inoratidza ARS-1620 seinomiririra chizvarwa chitsva cheKRASG12C-chaiyo inhibitors ine vimbiso yekurapa," akadaro munyori anotungamira, Matthew R Janes, PhD, kubva kuWespring Biosciences mu. San Diego, CA, uye vaunoshanda navo.
KRAS mutations ndiyo inonyanya kuchinjika oncogene uye tsvakiridzo yapfuura yakaratidza kuti angangoita makumi matatu muzana emamota ane RAS mutations. Kunyatsochinja kweKRAS kunotonga mukati memhando dzebundu. Semuyenzaniso KRASG12C is a predominant mutation mune isiri-diki cell cell cancer cancer (NSCLC), uye inowanikwawo mupancreatic uye colorectal adenocarcinomas.
Kunyangwe kuwanda uye makumi emakore ekutsvagisa anoratidza mutant KRAS semutyairi wepakati we tumorigenesis uye kuramba kwekiriniki, mutant KRAS yanga iri chinangwa chakasindimara.
Nzira dzakasiyana-siyana dzakaedza kuona mamorekuru madiki anonangana neKRAS, asi zvakakonzera kudzvinyirira kushoma kweKRAS mumaseru. Izvi zvakakurudzira vanyori kuti vagadzire komboni yekuvandudza KRAS-specific inhibitors, kusanganisira switch 2 pocket (S-IIP) KRASG12C inhibitors inosunga nekuita neGDP-yakasungwa mamiriro eKRAS, ichiteya mune isingashande conformation.
Kuti ibudirire, iyo inhibitor inofanira kuva nepamusoro potency uye kukurumidza kusunga kinetics. Iyo zvakare inofanirwa kuve neyakakwana pharmacokinetic zvivakwa kuchengetedza kuratidzwa uye kureba kwenguva yakareba yakakwana yekubata iyo GDP-yakasungwa isingashande mamiriro eKRAS ari kukurumidza nucleotide kutenderera.
Vaongorori vakagadzira uye vakagadzira ARS-1620 ine zvinodhaka-sezvivakwa, uye yakavandudza potency pamusoro pekutanga-chizvarwa makomisheni. Kushanda uye kinetics mumitsara yesero ine mutant allele zvakabva zvaongororwa kuti zvionekwe kana chinangwa chekuvharisa KRAS-GTP mumamota chaive chakakwana.
Kudzivirirwa kwekukura kwesero, pamwe chete nekugona kwekuita zvisiri izvo zvinogona kuratidza mukana wehupfu, zvakaongororwa.
Chekupedzisira, kuongorora kugarwa kwechinangwa mu vivo, yemuromo ARS-1620 yakapihwa mbeva dzakagadzika subcutaneous xenograft modhi dzine KRAS p.G12C sedoro rimwe chete, kana zuva nezuva kwemazuva mashanu.
Vatsvakurudzi vakashuma kuti ARS-1620 yakadzivisa zvakanyanya kukura kwebundu mune dosi- uye nguva-inotsamira nenzira ine yakanyorwa bundu regression.
Mune mashanu xenograft modhi yeNSCLC maseru mitsara mumakonzo, mamodheru ese akapindura mushure memavhiki maviri kusvika matatu ekurapwa, uye mana evashanu airatidza kudzvanyirirwa kwakanyanya kwebundu kukura. Uye zvakare, ARS-1620 yakatenderwa zvakanaka isina kucherechedzwa chepfu yekiriniki panguva yekurapa.
"Pamwe chete, humbowo hwemu vivo hwekuti ARS-1620 inoshanda zvakanyanya sechinhu chimwe chete muNSCLC modhi inopa humbowo hwepfungwa yekuti chikamu chakakosha chevarwere vane p.G12C KRAS mutations vanogona kubatsirwa kubva kuKRASG12C-inotungamirwa marapirwo," vakadaro vanyori.
Vakawedzera kuti ARS-1620 yakananga KRASG12C diki molecule inhibitor ine simba, inosarudza, nemuromo bioavailable, uye inoshivirirwa zvakanaka.
Nguva yekutumira: May-22-2018