Ukuphucula ukusebenza kwe-PROTAC: iSifundo esiQinisekisayo
Ukusetyenziswa kwe-molecule encinci ye-degraders, njenge-PROTACs (i-PROteolysis TArgeting Chimeras), imele isicwangciso sonyango sonyango ngokubangela ukuthotywa ngokukhawuleza kweeprotheni ezibangela izifo. Le ndlela inika umkhombandlela omtsha othembisayo wonyango lwezifo ezahlukeneyo, kubandakanya umhlaza.
Inkqubela phambili ebalulekileyo kule ndawo isanda kupapashwa kwijenali yoNxibelelwano lweNdalo ngoJulayi 2nd. Uphononongo, olukhokelwa liqela labaphandi, luchonge iindlela ezininzi zokubonisa iiselula ezilawula ukuthotywa okujoliswe kuko kweeprotheyini eziphambili ezifana ne-BRD4, BRD2/3, kunye ne-CDK9 isebenzisa ii-PROTAC.
Ukufumanisa ukuba ezi ndlela zangaphakathi zichaphazela njani ukuthotywa kweprotheyini, abaphandi bahlolisise utshintsho kwi-BRD4 yokuthotywa kobukho okanye ukungabikho kwe-MZ1, i-CRL2VHL-based BRD4 PROTAC. Iziphumo zibonise ukuba iindlela ezahlukeneyo zeselula zangaphakathi zinokuthintela ngokuzenzekelayo ukuthotywa kwe-BRD4 ekujoliswe kuyo, okunokuthi kuthintelwe zizithinteli ezithile.
Iziphumo eziphambili:Abaphandi baqinisekisa iikhompawundi ezininzi njengezixhasi zokuthotywa, kubandakanywa iPDD00017273 (i-PARG inhibitor), i-GSK2606414 (i-PERK inhibitor), kunye ne-luminespib (i-HSP90 inhibitor). Ezi ziphumo zibonisa ukuba iindlela ezininzi zeseli zangaphakathi zinefuthe ekusebenzeni kokuthotywa kweprotein kumanyathelo ahlukeneyo.
Kwiiseli ze-HeLa, kwabonwa ukuba i-PARG inhibition yi-PDD inokunyusa kakhulu ukuthotywa okujoliswe kuyo kwe-BRD4 kunye ne-BRD2 / 3 kodwa kungekhona i-MEK1 / 2 okanye i-ERα. Uhlalutyo olongezelelweyo lubonise ukuba i-PARG inhibition ikhuthaza ukusekwa kwe-BRD4-MZ1-CRL2VHL ternary complex kunye ne-K29/K48-edityaniswe kwindawo yonke indawo, ngaloo ndlela iququzelela inkqubo yokuthotywa. Ukongeza, inhibition ye-HSP90 yafunyanwa yokuphucula ukuthotywa kwe-BRD4 emva kokuhlala kwindawo yonke.
Ukuqonda ngoomatshini:Uphononongo luphonononge iindlela eziphantsi kwezi ziphumo, lutyhila ukuba i-PERK kunye ne-HSP90 inhibitors ziindlela eziphambili eziphembelela ukuthotywa kweprotein ngenkqubo ye-ubiquitin-proteasome. Ezi inhibitors zimodareyitha amanyathelo ahlukeneyo kwinkqubo yokuthotywa okubangelwa yimichiza yeekhemikhali.
Ngaphaya koko, abaphandi baphanda ukuba ngaba iziphuculi ze-PROTAC zinokunyusa ukusebenza kakuhle kwabathomalalisi abanamandla. I-SIM1, i-PROTAC esandul 'ukuphuhliswa kwe-trivalent, iboniswe ukuba ikhuthaze ngokufanelekileyo ukusekwa kwe-BRD-PROTAC-CRL2VHL kunye nokuthotywa okulandelayo kwe-BRD4 kunye ne-BRD2 / 3. Ukudibanisa i-SIM1 kunye nePDD okanye i-GSK kubangele ukufa kweeseli okusebenzayo kunokusebenzisa i-SIM1 yodwa.
Uphononongo lukwafumanise ukuba i-PARG inhibition inokuthoba ngokufanelekileyo kungekuphela nje iiproteni zosapho lwe-BRD kodwa kunye ne-CDK9, iphakamisa ukusetyenziswa okubanzi kwezi ziphumo.
Iimpembelelo zexesha elizayo:Ababhali bophononongo balindele ukuba ukuhlolwa okuqhubekayo kuya kuchonga iindlela ezongezelelweyo zeselula ezifaka isandla ekuqondeni iindlela ezijoliswe kuzo zokunciphisa iiprotheyini. Olu lwazi lunokukhokelela kuphuhliso lwezicwangciso eziliqili zonyango olusebenzayo kuluhlu lwezifo.
Isalathiso:UYuki Mori et al. Iindlela zokubonisa kwangaphakathi zimodareyitha ukuthotywa kweprotheyini ekujoliswe kuyo. Unxibelelwano ngeNdalo (2024). Inqaku elipheleleyo https://www.nature.com/articles/s41467-024-49519-z
Olu phononongo oluyimpumelelo lugxininisa amandla e-PROTAC kwizicelo zonyango kwaye lugxininisa ukubaluleka kokuqonda iindlela zokubonisa iiselula ukunyusa ukusebenza kweprotheyini ekujoliswe kuyo.