Kuvandudza Kubudirira kwePROTAC: Chidzidzo Chinoputsa

Kushandiswa kwemamorekuru madiki anodzikisira, akadai sePROTACs (PROteolysis TArgeting Chimeras), inomiririra nzira itsva yekurapa nekukonzera kushatisa nekukurumidza kwemapuroteni anokonzera chirwere. Iyi nzira inopa nzira itsva inovimbisa yekurapa zvirwere zvakasiyana-siyana, kusanganisira gomarara.

Kufambira mberi kwakakosha mundima iyi kwakangoburitswa mujenari Nature Communications musi waChikunguru 2nd. Chidzidzo ichi, chakatungamirwa nechikwata chevatsvaguri, chakaratidza nzira dzinoverengeka dzemaserura dzinoronga kudzikira kwakanangwa kwemapuroteni akakosha akadai seBRD4, BRD2/3, uye CDK9 vachishandisa PROTACs.

Kuti uone kuti nzira idzi dzemukati dzinokanganisa sei kuparara kweprotein, vatsvakurudzi vakaongorora kuchinja kweBRD4 kuora muhupo kana kusavapo kweMZ1, CRL2VHL-based BRD4 PROTAC. Zvakawanikwa zvakaratidza kuti nzira dzakasiyana-siyana dzemukati dzemaserura dzinogona kuvharira BRD4-yakananga kudzikisira, iyo inogona kurwiswa nemainhibitors chaiwo.

Zvakawanikwa Zvinokosha:Vatsvakurudzi vakasimbisa makomisheni akati wandei seanowedzera degradation, anosanganisira PDD00017273 (a PARG inhibitor), GSK2606414 (a PERK inhibitor), uye luminespib (an HSP90 inhibitor). Mhedzisiro iyi inoratidza kuti akawanda emukati ma cellular nzira anokanganisa kushanda kweprotein degradation pamatanho akasiyana.

Mumasero eHeLa, zvakaonekwa kuti PARG inhibition nePDD inogona kuwedzera zvakanyanya kuderedzwa kwakanangwa kweBRD4 uye BRD2/3 asi kwete kweMEK1/2 kana ERα. Kumwe kuongorora kwakaratidza kuti PARG inhibition inokurudzira kuumbwa kweBRD4-MZ1-CRL2VHL ternary complex uye K29/K48-yakabatana ubiquitination, nokudaro kufambisa maitiro ekuora. Pamusoro pezvo, HSP90 inhibition yakawanikwa kusimudzira BRD4 kuderedzwa post-ubiquitination.

Mechanistic Insights:Chidzidzo ichi chakaongorora maitiro ari pasi pemhedzisiro iyi, zvichiratidza kuti PERK neHSP90 inhibitors inzira dzekutanga dzinopesvedzera kuparara kweprotein kuburikidza neubiquitin-proteasome system. Aya inhibitors anogadzirisa matanho akasiyana-siyana mukuora mwoyo kunokonzerwa nemakemikari emakemikari.

Uyezve, vatsvakurudzi vakaongorora kana PROTAC ekuwedzera inogona kuwedzera kushanda kwevanoderedza zvine simba. SIM1, ichangoburwa trivalent PROTAC, yakaratidzwa kuti iwedzere zvinobudirira kuumba iyo BRD-PROTAC-CRL2VHL yakaoma uye yakatevera kushatiswa kweBRD4 uye BRD2/3. Kubatanidza SIM1 nePDD kana GSK kwakakonzera kufa kwakanyanya kwesero pane kushandisa SIM1 chete.

Chidzidzo ichi zvakare chakawana kuti PARG inhibition inogona kunyatso kudzikisa kwete chete mapuroteni emhuri yeBRD asiwo CDK9, zvichiratidza kushanda kwakakura kwezviwanikwa izvi.

Zvinoreva Remangwana:Vanyori vechidzidzo vanofungidzira kuti kumwe kutariswa kucharatidza nzira dzekuwedzera dzemaserura dzinobatsira mukunzwisisa kweanonangwa mapuroteni ekuderedza maitiro. Mafungiro aya anogona kutungamira mukugadzirwa kwemaitiro anoshanda ekurapa ezvirwere zvakasiyana.

Reference:Yuki Mori et al. Intrinsic signing pathways modulate yakanangwa protein degradation. Nature Communications (2024). Chinyorwa chizere https://www.nature.com/articles/s41467-024-49519-z

Ichi chidzidzo chebudiriro inosimbisa kugona kwePROTACs mukurapa kwekushandisa uye inosimbisa kukosha kwekunzwisisa cellular masaini nzira kuti uwedzere kushanda kwekunangwa kweprotein degradation.