Te Whakapai Ake i te Whai Huatanga o PROTAC: He Rangahau Hou

Ko te whakamahinga o ngā mea whakaiti ngota iti, pērā i ngā PROTAC (PROteolysis TArgeting Chimeras), he rautaki rongoā hou mā te whakaoho i te tere o te whakahekenga o ngā pūmua e puta ai te mate. Ka tukuna e tēnei huarahi he huarahi hou e whai hua ana mō te rongoā i ngā momo mate, tae atu ki te mate pukupuku.

Nō nā tata nei i whakaputaina ai tētahi whanaketanga nui i roto i tēnei mara i roto i te puka Nature Communications i te 2 o Hūrae. Nā te rangahau, i arahina e tētahi rōpū kairangahau, i tautuhia ētahi ara tohu pūtau e whakahaere ana i te whakahekenga whai take o ngā pūmua matua pērā i te BRD4, BRD2/3, me te CDK9 mā te whakamahi i ngā PROTAC.

Hei whakatau i te pānga o ēnei ara ā-roto ki te pirau o te pūmua, i tirotirohia e ngā kairangahau ngā panoni o te pirau o te BRD4 i te aroaro, i te ngaro rānei o te MZ1, he BRD4 PROTAC e hangai ana ki te CRL2VHL. I whakaatuhia e ngā kitenga he maha ngā ara ā-roto pūtau ka aukati i te pirau e arohia ana e te BRD4, ka taea te ārai mā roto i ngā aukati motuhake.

Ngā Kitenga Matua: I whakamanahia e ngā kairangahau ētahi matū hei whakarei ake i te pirau, tae atu ki te PDD00017273 (he aukati PARG), te GSK2606414 (he aukati PERK), me te luminespib (he aukati HSP90). E whakaatu ana ēnei hua he maha ngā ara pūtau ā-roto e pā ana ki te whai huatanga o te pirau pūmua i ngā taahiraa rerekē.

I roto i ngā pūtau HeLa, i kitea ko te aukati PARG e te PDD ka taea te whakanui ake i te whakahekenga kua whakaritea o BRD4 me BRD2/3 engari kāore i te MEK1/2, o ERα rānei. I whakaatuhia e ngā tātaritanga anō ko te aukati PARG ka whakatairanga i te hanganga o te matatini tuatoru BRD4-MZ1-CRL2VHL me te ubiquitination hono-K29/K48, ā, nā reira ka āwhina i te tukanga whakahekenga. I tua atu, i kitea ko te aukati HSP90 ka whakanui ake i te whakahekenga o BRD4 i muri i te ubiquitination.

Ngā Tirohanga Ā-Mīhini: I tūhuratia e te rangahau ngā tikanga e pā ana ki ēnei pānga, e whakaatu ana ko ngā aukati PERK me HSP90 ngā ara matua e awe ana i te pirau pūmua mā te pūnaha ubiquitin-proteasome. Ka whakarerekēhia e ēnei aukati ngā taahiraa rerekē o te tukanga pirau i puta mai i ngā matū.

I tua atu, i rangahauhia e ngā kairangahau mēnā ka taea e ngā whakarei PROTAC te whakanui ake i te whai huatanga o ngā kaiwhakaiti kaha. I whakaaturia ko SIM1, he PROTAC trivalent i hangaia tata nei, he kaha ake te whakaoho i te hanganga o te matatini BRD-PROTAC-CRL2VHL me te whakahekenga o BRD4 me BRD2/3 i muri mai. Ko te whakakotahi i a SIM1 me te PDD, GSK rānei i hua ake ai te mate pūtau whai hua ake i te whakamahi i a SIM1 anake.

I kitea anō hoki e te rangahau ka taea e te aukati a PARG te whakangaro i ngā pūmua o te whānau BRD me te CDK9 anō hoki, e whakaatu ana i te whānui ake o te whakamahinga o ēnei kitenga.

Ngā Pānga o te Ao kei te heke mai: E matapaetia ana e ngā kaituhi o te rangahau mā ngā tirotiro anō ka kitea ētahi atu ara pūtau e whai wāhi ana ki te māramatanga ki ngā tikanga pakaru pūmua kua arotahihia. Mā ēnei māramatanga ka ārahi pea ki te whakawhanake i ngā rautaki rongoā whai hua ake mō ngā momo mate.

Tohutoro: Yuki Mori me ētahi atu. Ka whakarerekē ngā ara tohu ā-roto i te pirau pūmua kua tohua. Nature Communications (2024). te tuhinga katoa https://www.nature.com/articles/s41467-024-49519-z

E whakaatu ana tēnei rangahau hou i te pūmanawa o ngā PROTAC i roto i ngā mahi rongoā, ā, e whakaatu ana hoki i te hiranga o te mārama ki ngā ara tohu pūtau hei whakarei ake i te whai huatanga o te whakapōrearea pūmua kua arotahihia.