Kuzamura Ingaruka za PROTAC: Inyigisho Yibanze
Ikoreshwa rya molekile ntoya, nka PROTACs (PROteolysis TArgeting Chimeras), byerekana ingamba zo kuvura udushya zitera kwangirika vuba kwa poroteyine zitera indwara. Ubu buryo butanga icyerekezo gishya cyo kuvura indwara zitandukanye, harimo na kanseri.
Iterambere rikomeye muri uru rwego riherutse gusohoka mu kinyamakuru Nature Communications ku ya 2 Nyakanga. Ubushakashatsi buyobowe nitsinda ryabashakashatsi, bwerekanye inzira nyinshi zerekana ibimenyetso byerekana ingirabuzimafatizo zigenga iyangirika rya poroteyine zingenzi nka BRD4, BRD2 / 3, na CDK9 ukoresheje PROTACs.
Kugirango hamenyekane uburyo izi nzira zinyuranye zigira ingaruka ku iyangirika rya poroteyine, abashakashatsi bagenzuye impinduka zo kwangirika kwa BRD4 imbere ya MZ1 cyangwa idahari, CRL2VHL ishingiye kuri BRD4 PROTAC. Ibyavuye mu bushakashatsi byagaragaje ko inzira zinyuranye zigenda zishobora guhita zibuza BRD4 kwangirika kwangirika, gushobora guhangana na inhibitori yihariye.
Ibisubizo by'ingenzi:Abashakashatsi bemeje ibice byinshi byongera imbaraga zo gutesha agaciro, harimo PDD00017273 (inhibitor ya PARG), GSK2606414 (inhibitor ya PERK), na luminespib (inhibitor ya HSP90). Ibisubizo byerekana ko inzira nyinshi zifata inzira zigira ingaruka kumikorere ya poroteyine ku ntambwe zitandukanye.
Mu tugari twa HeLa, byagaragaye ko kubuza PARG na PDD bishobora kuzamura cyane iyangirika rya BRD4 na BRD2 / 3 ariko ntabwo ari MEK1 / 2 cyangwa ERα. Isesengura ryakozwe ryagaragaje ko kubuza PARG guteza imbere ishingwa rya BRD4-MZ1-CRL2VHL ternary complex hamwe na K29 / K48 bifitanye isano na hose, bityo bikorohereza inzira yo gutesha agaciro. Byongeye kandi, HSP90 yabujijwe yabonetse kugirango yongere BRD4 iyangirika nyuma yubuzima bwose.
Ubushishozi:Ubushakashatsi bwerekanye uburyo bushingiye kuri izo ngaruka, bugaragaza ko inzitizi za PERK na HSP90 ari inzira zambere zigira ingaruka ku iyangirika rya poroteyine binyuze muri sisitemu ya ubiquitin-proteasome. Izi inhibitor zihindura intambwe zitandukanye murwego rwo kwangirika guterwa nubumara bwimiti.
Byongeye kandi, abashakashatsi bakoze ubushakashatsi niba abongera PROTAC bashobora kuzamura imikorere yangirika. SIM1, PROTAC iherutse gutunganywa, yerekanwe kugirango irusheho gutera ishingwa rya BRD-PROTAC-CRL2VHL hamwe no kwangirika kwa BRD4 na BRD2 / 3. Guhuza SIM1 na PDD cyangwa GSK byaviriyemo gupfa neza kuruta gukoresha SIM1 wenyine.
Ubushakashatsi bwagaragaje kandi ko kubuza PARG bishobora gutesha agaciro poroteyine zo mu muryango wa BRD gusa ndetse na CDK9, byerekana ko ubushakashatsi bwagutse.
Ingaruka z'ejo hazaza:Abanditsi b'ubwo bushakashatsi bateganya ko ibindi bizagerwaho bizagaragaza inzira zinyuranye zigira uruhare mu gusobanukirwa uburyo bwo kwangirika kwa poroteyine. Ubu bushishozi bushobora kuganisha ku gushyiraho ingamba zifatika zo kuvura indwara zitandukanye.
Reba:Yuki Mori n'abandi. Inzira yerekana ibimenyetso byerekana poroteyine igabanuka. Itumanaho rya Kamere (2024). ingingo yuzuye https://www.umuco.com/articles/s41467-024-49519-z
Ubu bushakashatsi bwimbitse bushimangira ubushobozi bwa PROTACs muburyo bwo kuvura kandi bugaragaza akamaro ko gusobanukirwa inzira zerekana ibimenyetso bya selile kugirango byongere imbaraga zo kwangirika kwa poroteyine.