ARS-1620: Cholepheretsa chatsopano cha khansa ya KRAS-mutant

Malinga ndi kafukufuku wofalitsidwa muCell,ofufuza apanga choletsa chapadera cha KRASG12C chotchedwa ARS-1602 chomwe chimapangitsa kuti chotupa chichuluke mu mbewa.

"Kafukufukuyu akupereka umboni wotsimikizika kuti mutant KRAS ikhoza kuyang'aniridwa mwachisawawa, ndikuwulula kuti ARS-1620 ikuyimira m'badwo watsopano wa KRASG12C-specific inhibitors omwe ali ndi mwayi wochiritsa," adatero wolemba wamkulu, Matthew R Janes, PhD, wochokera ku Wellspring Biosciences ku. San Diego, CA, ndi anzawo.

Kusintha kwa KRAS ndizomwe zimasinthidwa kwambiri pa oncogene ndipo kafukufuku wam'mbuyomu wawonetsa kuti pafupifupi 30% ya zotupa zimakhala ndi masinthidwe a RAS. Kusintha kwapadera kwa KRAS kumayang'anira mitundu ina ya chotupa. Mwachitsanzo KRASG12C ndikusintha kwakukulu kwa khansa yosakhala yaying'ono ya m'mapapo (NSCLC), ndipo imapezekanso mu pancreatic and colorectal adenocarcinomas.

Ngakhale kufalikira komanso zaka makumi angapo za kafukufuku wowonetsa mutant KRAS ngati woyendetsa wamkulu wa tumorigenesis ndi kukana kwachipatala, mutant KRAS wakhala chandamale chaukali.

Njira zosiyanasiyana zayesera kuzindikira mamolekyu ang'onoang'ono omwe amayang'ana KRAS, koma apangitsa kuti KRAS ikhale yochepa m'maselo. Izi zidalimbikitsa olemba kupanga gulu lothandizira zoletsa zoletsa za KRAS, kuphatikiza ma switch 2 pocket (S-IIP) KRASG12C inhibitors omwe amamangiriza ndikuchitapo kanthu ndi dziko lomangidwa ndi GDP la KRAS, ndikuliyika mosagwirizana.

Kuti ikhale yogwira mtima, inhibitor iyenera kukhala ndi potency yayikulu komanso kinetics yomanga mwachangu. Iyeneranso kukhala ndi zinthu zabwino kwambiri za pharmacokinetic kuti zisunge mawonekedwe ndi nthawi kwa nthawi yayitali yokwanira kuti igwire dziko la KRAS lomwe silinagwire ntchito la GDP lomwe likuyenda mwachangu kuzungulira kwa nucleotide.

Ofufuzawo adapanga ndi kuphatikizira ARS-1620 yokhala ndi zinthu zonga mankhwala, ndikuwonjezera mphamvu pamagulu am'badwo woyamba. Kuchita bwino komanso ma kinetics pamizere yama cell okhala ndi mutant allele adawunikidwa kuti adziwe ngati zomwe mukufuna kuletsa KRAS-GTP muzotupa zinali zokwanira.

Kuletsa kukula kwa maselo, komanso kuthekera kwa zochitika zina zomwe zingasonyeze kuthekera kwa poizoni, zinayesedwa.

Pomaliza, kuti awone kuchuluka kwa anthu omwe akufuna kukhala mu vivo, oral ARS-1620 idaperekedwa kwa mbewa zokhala ndi ma subcutaneous xenograft okhala ndi KRAS p.G12C ngati mlingo umodzi, kapena tsiku lililonse kwa masiku asanu.

Ofufuzawo adanenanso kuti ARS-1620 idalepheretsa kwambiri kukula kwa chotupa pamlingo wodalira nthawi komanso motengera nthawi yokhala ndi chotupa chodziwika bwino.

M'mitundu isanu ya xenograft yama cell a NSCLC mu mbewa, mitundu yonse idayankha patatha milungu iwiri kapena itatu yamankhwala, ndipo anayi mwa asanuwo adawonetsa kuponderezedwa kwakukulu kwakukula kwa chotupa. Komanso, ARS-1620 anali bwino analekerera popanda anaona matenda kawopsedwe pa nthawi ya mankhwala.

"Pamodzi, umboni wa mu vivo wosonyeza kuti ARS-1620 ndiyothandiza kwambiri ngati wothandizira m'modzi pamitundu yonse ya NSCLC umapereka umboni wakuti gawo lalikulu la odwala omwe ali ndi kusintha kwa p.G12C KRAS atha kupindula ndi machiritso opangidwa ndi KRASG12C," adatero olembawo.

Ananenanso kuti ARS-1620 ndi KRASG12C yachindunji yoletsa mamolekyu ang'onoang'ono omwe ali amphamvu, osankha, opezeka pakamwa, komanso amalekerera bwino.