闄嶈В灏嶆瘮鎶戝埗锛氶枊鐧奸澏鍚�3-缇ュ熀-3-鐢插熀-鎴婁簩閰拌紨閰禔閭勫師閰剁殑闄嶈В灏�鍒嗗瓙
4鏈�22鏃ワ紝楗掔噺瑾查绲勮垏姝︽饥澶у瀹嬩繚浜椤岀祫鍚堜綔鍦ㄣ€婅棩鐗╁寲瀛搁洔蹇椼€嬶紙Journal of Medicinal Chemistry锛夌櫦琛ㄩ鐐衡€滈檷瑙e皪姣旀姂鍒讹細闁嬬櫦闈跺悜3-缇ュ熀-3-鐢插熀-鎴婁簩閰拌紨閰禔閭勫師閰剁殑闄嶈В灏忓垎瀛愨€濓紙Degradation Versus Inhibition: Development of Proteolysis-Targeting Chimeras for Overcoming Statin-Induced Compensatory Upregulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase锛夌殑鐮旂┒璜栨枃銆侶MGCR锛�3-Hydroxy-3-methylglutaryl Coenzyme A Reductase锛夋槸鑶藉浐閱囷紙 cholesterol锛夊悎鎴愰€斿緫涓殑闄愰€熼叾锛屽苟涓旀槸缍撳吀鐨勬不鐧傝鑴傜暟甯哥殑钘ョ墿闈堕粸銆傚畠鐨勬姂鍒跺姂锛� statin,浠栨眬椤炲寲鍚堢墿锛夊闃夸紣浠栨眬锛坅torvastatin,绔嬫櫘濡�?锛岃紳鐟烇級鍦ㄨ嚚搴婅鐢ㄤ簬闋愰槻鍜屾不鐧傚績琛€绠$柧鐥咃紝骞跺彇寰椾簡妤靛ぇ鐨勬垚鍔熴€備絾鏄湁鐩哥暥涓€閮ㄥ垎浜哄皪浠栨眬椤炶棩鐗╀笉鑰愬彈锛屾瘮濡傛渻鐧肩敓楠ㄩ鑲屾悕鍌风瓑杓冪偤鍤撮噸鐨勫壇浣滅敤锛岄€欐湁鍙兘鑸囨湇鐢ㄤ粬姹€椤炶棩鐗╁悗楂斿収閫氶亷璨犲弽楗嬭绡€灏庤嚧HMGCR瑁滃劅鎬ц〃閬斿崌楂樻湁闂溿€傚洜鑰屽湪瑭插伐浣滀腑锛岀爺绌朵汉鍝″埄鐢ㄨ泲鐧介澏鍚戦檷瑙e祵鍚堥珨锛圥roteolysis-Targeting Chimera, PROTAC锛夌殑鎶€琛擄紝灏岺MGCR鍦ㄩ€茶闄嶈В鑰岃捣鍒版姂鍒惰喗鍥洪唶鍚堟垚浣滅敤鐨勫悓鏅傚彲浠ラ伩鍏岺MGCR鐨勯珮琛ㄩ仈锛屽緸鑰屾湁鏈涢檷浣庡壇浣滅敤銆� 鍦�1.鎶戝埗鍔戣垏PROTAC灏岺MGCR鐨勫奖闊垮湪瑭插伐浣滀腑锛岀爺绌朵汉鍝¢鍏堢閬稿嚭SRD15绱拌優绯讳綔鐐虹窗鑳炴脯瑭︾殑鍩虹锛岀劧鍚庡熀浜嶩MGCR鐨勯厤楂旈樋浼愪粬姹€鍜孍3閺堟帴閰禖RBN鐨勯厤楂旀硦棣浮鑳洪€茶浜嗕竴绯诲垪鐨勬鏁堥棞绯荤爺绌讹紝鐧肩従鍖栧悎鐗㏄22A浣滅偤PROTAC鍏锋湁杓冨ソ鍦伴檷瑙f椿鎬э紙DC50~100 nM锛夈€傜浉姣斾箣涓嬶紝鎶戝埗鍔戦樋浼愪粬姹€灏岺MGCR寮曡捣浜嗘槑椤殑涓婅浣滅敤锛堝湒1锛夈€� 鍦�2.鎶戝埗鍔戝拰PROTAC灏峀DLR鍜岃喗鍥洪唶鐨勫奖闊挎帴涓嬩締锛岀爺绌朵汉鍝¢€氶亷涓€绯诲垪鐨勭敓鍖栧拰绱拌優鐢熺墿瀛稿椹楄瓑瀵︿簡PROTAC閫氶亷娉涚礌-铔嬬櫧閰堕珨绯荤当鐧兼彯浣滅敤鐨勬鍒讹紱閫氶亷铔嬬櫧绲勫鐨勭爺绌剁櫦鐝炬姂鍒跺姂鍜孭ROTAC寮曡捣鐨勭祫瀛告噳绛斾篃鏈夊緢澶т笉鍚屻€傛姂鍒跺姂鍜孭ROTAC灏嶈喗鍥洪唶鍚堟垚鎶戝埗鍜岄€氶亷SREBP閫氳矾寮曡捣鐨勪綆瀵嗗害鑴傝泲鐧藉彈楂旓紙LDLR锛夎〃閬旀按骞充笂瑾跨殑鑳藉姏鐩哥暥锛堝湒2锛夈€侶MGCR鏄綅浜庡収璩恫涓婄殑鍏璺ㄨ啘铔嬬櫧, PROTAC灏嶆椤炶泲鐧界殑闄嶈В鑳藉姏寰€寰€鏈夐檺锛岃┎宸ヤ綔棣栨璀夋槑鍒╃敤PROTAC鎶€琛撳皪鍏ц唱缍茶泲鐧介€茶闄嶈В鐨勫彲琛屾€с€傚彟澶栵紝闈惰泲鐧戒笂瑾跨殑鐝捐薄閭勫嚭鐝惧湪寰堝鍏跺畠鐨勬姂鍒跺姂涓紝瑭插伐浣滃睍绀轰簡闈㈠皪姝ょó鎯呮硜鏅傛槸PROTAC涓€鍊嬪緢濂界殑鎳夌敤鍫存櫙銆傚畫淇濅寒瑾查绲勫崥澹敓鏉庣編娆e拰楗掔噺绲勫崥澹悗妤婃瘏鎱剁偤鏈伐浣滃叡鍚岀涓€浣滆€咃紝楗掔噺鍜屽畫淇濅寒瑾查绲勭緟濠曠偤鍏卞悓閫氳▕浣滆€呫€傛湰鐮旂┒寰楀埌浜嗗湅瀹惰嚜鐒剁瀛稿熀閲戙€佹竻鑿�-鍖楀ぇ鐢熷懡鑱悎涓績浠ュ強涓湅鍗氬+鍚庡熀閲戠殑澶у姏鏀寔銆傚師鏂囬張鎺ワ細https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00339
娓呰彲澶у
2021-04-11