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Nat Chem Biol 2014, 10(1): 29锛夈€備笓鍒╂枃鐚腑浠嬬粛浜嗚鍖栧悎鐗 (WO 2013043001)銆娌荤枟鐧岀棁鐨勫彉鏋勫皬鍒嗗瓙纾烽吀閰舵姂鍒跺墏闂笘 GlaxoSmithKline 鍏徃鎶ラ亾鍒舵垚浜嗕竴绉嶅彛鏈嶆湁鏁堢殑閲庣敓鍨 p53-璇卞铔嬬櫧纾烽吀閰 1 (PP2C-delta)寮傛瀯鎶戝埗鍓 GSK-2830371, 缁忎复搴婂墠鐮旂┒纭畾浜嗗叾鐗圭偣锛屽湪娲讳綋澶栨垨娲讳綋鍐呴兘鍙姂鍒惰偪鐦ょ粏鑳炵敓闀裤€傝繖绉嶈泲鐧界７閰搁叾鐢 PPM1D 鍩哄洜缂栫爜锛屽緢澶氱檶鐥囦腑閮芥湁鎵╁锛屽叾杩囪〃杈句笌鑲跨槫褰㈡垚鏈夊叧銆傜爺绌朵汉鍛樺紑鍙戜簡涓€绯诲垪绉颁箣涓?甯界姸姘ㄥ熀閰?鐨勫皬鍒嗗瓙铔嬬櫧纾烽吀閰跺紓鏋勬姂鍒跺墏锛屽叾缁勬垚鍖呮嫭姘ㄥ熀閰告牱鏍稿績鍙婁晶闈㈢殑鍙慨楗板熀鍥€傝繖浜涘熀鍥笌铔嬬櫧纾烽吀閰剁嫭鐗圭殑鐡ｇ姸缁撴瀯鍩熷叿鏈夐珮浜插悎鍔涖€侴SK-2830371 鐗瑰紓鎬у己鏁堟姂鍒朵簡纾?p38 涓濊鍘熸椿鍖栬泲鐧芥縺閰剁殑 PP2C-未鑴辩７閰革紝IC50 涓 13 nM銆傝〃鐜版湁 PPM1D-鎵╁缁嗚優绯荤殑涔宠吅鐧屻€佹穻宸寸槫鍜屾€ユ€ф穻宸存瘝缁嗚優鐧借鐥呬腑锛孏SK-2830371 浠ユ祿搴︿緷璧栨柟寮忓彲閫嗘€у鍔犱簡铔嬬櫧纾烽吀閰跺簳鐗╃殑纾烽吀鍖栥€傚湪 PPM1D-鎵╁ TP53 閲庣敓鍨嬩汉涔宠吅鐧 MX-1 鎴 MCF7 缁嗚優涓紝GSK-2830371 寮曞彂浜嗘祿搴︿緷璧栨€х敓闀挎姂鍒躲€備笌姝ょ浉鍙嶏紝鍦 PPM1D-鎵╁ p53-绐佸彉涔宠吅瀵肩鐧 BT-474 缁嗚優涓紝GSK-2830371 鍗村鍏嬮殕褰㈡垚鏃犱綔鐢ㄣ€傛澶栵紝GSK-2830371 鎶戝埗浜嗛殣钘忔湁閲庣敓鍨 TP53 娣嬪反鏍风粏鑳炵郴鐨勫娈栵紝鎻愮ず铔嬬櫧纾烽吀閰舵姂鍒剁殑鎶楃敓闀夸綔鐢ㄦ槸鐢 p53 娲诲寲鎵€浠嬪鐨勩€傚紓绉嶇Щ妞 PPMID-鍓湰鐨勫皬榧犻潪闇嶅閲 B 缁嗚優 (DoHH2) 涓紝鍙ｆ湇 GSK-2830371 浣 p53 鐨勭７閰稿寲寤堕暱浜 6 灏忔椂锛屼笌鍏跺湪灏忛紶浣撳唴鍗婅“鏈熻緝鐭竴鑷淬€傛瘡鏃ヤ娇鐢ㄤ袱娆℃垨涓夋 GSK-2830371 (150 mg/kg)锛屽垎鍒娇鑲跨槫鐢熼暱鎶戝埗浜 41% 鍜 68%銆傝泲鐧界７閰搁叾鎶戝埗瀵艰嚧纾烽吀搴曠墿 p53 鍜 Chk2 鏄庢樉澧炲姞鍙婅泲鐧界７閰搁叾娴撳害闄嶄綆锛圙ilmartin, A.G. et al. Nat Chem Biol 2014, Advanced publication锛夈€ 涓撳埄鏂囩尞涓粙缁嶄簡璇ュ寲鍚堢墿 (WO 2012149102)銆 KARYOPHARM 鍏徃浠 PAK-4 娌荤枟鑳拌吅鐧屼綔涓虹洰鏍 Karyopharm 鍏徃鐮旂┒浜哄憳寮€鍙戜簡涓濇皑閰?鑻忔皑閰歌泲鐧芥縺閰 PAK 4 (PAK-4) 鐨勫彉鏋勮皟鑺傚墏锛屼复搴婂墠璇曢獙涓娌荤枟鑳拌吅鐧岃〃鐜板嚭甯屾湜銆傝繖浜涘寲鍚堢墿鍦ㄨ儼鑵虹檶缁嗚優涓〃鐜板嚭鎶楀娈栨椿鎬э紙IC50 < 250 nM锛夛紝鍗翠笉浼氬奖鍝嶆甯镐汉浣撹儼绠′笂鐨粏鑳炪€傚湪娲讳綋澶栫爺绌朵腑锛孠PT-7189 涓 PAK-4 铔嬬櫧琛ㄨ揪闄嶄綆鍙婃姉鍑嬩骸淇″彿浼犻€掗€嗚浆鏈夊叧锛孭AK4 RNA 骞叉壈鍒欏寮轰簡 KPT-7189 鐨勬椿鎬с€侹PT-7189 鎶戝埗浜嗘惡甯︾檶鐥囧共缁嗚優鏍囪鐗╁苟楂樺害鑰愯嵂鑳拌吅鐧岀粏鑳炲舰鎴愮悆鐘朵綋鐨勮兘鍔涳紝涓庝竴绉嶄笂鐨埌闂磋川琛ㄥ瀷鐩哥銆傚彟涓€绉 PAK-4 鍙樻瀯璋冭妭鍓 KPT-7651 鍦ㄥ皬榧犱腑琛ㄧ幇鍑 95% 鐨勫彛鏈嶇敓鐗╁埄鐢ㄥ害锛屽苟鍙壇濂借€愬彈锛屾渶楂樿€愬彈鍙ｆ湇鍓傞噺鏄 60 mg/kg銆傜洰鍓嶆鍦ㄥ鐨笅銆佸父浣嶅拰 LSL-KrasG12D/+銆丩SL-Trp53R172H/+銆丳dx-1-Cre 杞熀鍥犲皬榧犲紑灞曡繘涓€姝ヨ皟鏌 (Azmi, A.S. et al. Gastrointest Cancers Symp (Jan 16-18, San Francisco) 2014, Abst 233)銆侴astrointest Cancers Symp (Jan 16-18, San Francisco) 2014, Abst 233). GLAXOSMITHKLINE 鎶ラ亾娌荤枟澶氬彂鎬ч楂撶槫鐨勬柊鍨嬫姉浣鈥鑽墿缁撳悎鐗 GSK-2857916锛圝6M0-mcMMAF锛汫laxoSmithKline锛夋槸涓€绉嶆柊鍨嬩汉鍖 Fc-鏀归€犳姉 B-缁嗚優鎴愮啛鎶楀師鈥鍗曠敳鍩哄ゥ閲屾柉浠栨眬 (auristatin) F 鍗曞厠闅嗘姉浣 (MAb)鈥鑽墿缁撳悎鐗╋紝鎷熺敤浜庢不鐤楀鍙戞€ч楂撶槫 (MM)锛屽凡瀹炴柦浜嗕复搴婂墠鐮旂┒璇勪环鍏舵椿鎬с€侴SK-2857916 瀵 TNF 閰嶄綋瓒呭鏃忔垚鍛?3B (BAFF) 鍜 13 (APRIL) 鐨 IC50 鍒嗗埆涓 0.91 鍜 2.43 mcg/mL銆備笌 J6M0-vcMMAE 鐩告瘮锛屽彂鐜 GSK-2857916 鏁堟灉鏇村己锛孖C50 鍊煎垎鍒负 11.5 鍜 55.8 ng/mL銆侴SK-2857916 闃绘柇浜 MM 缁嗚優鐨勭敓闀垮拰瀛樻椿銆備笌楠ㄩ珦鍩鸿川缁嗚優涓€璧峰煿鍏伙紝GSK-2857916锛?銆?.001銆?.01銆?.1銆?.0 鍜 10 mcg/mL锛夐€夋嫨鎬ф姂鍒朵簡缁嗚優娲诲姏銆備笌 J6M0-姝ｅ父 Fc 鐩告瘮鏃讹紝J6M0-mcMMAF 瀵规姉浣撲緷璧栫粏鑳炰粙瀵肩粏鑳炴瘨鎬х殑璇卞浣滅敤鏇村己銆備娇鐢 J6M0-mcMMAF锛屾偅鑰呰嚜浣 MM 缁嗚優婧惰В鏄庢樉澧炲銆傚甫鏈 H929 鍜 OPM2 缁嗚優绯诲紓绉嶇Щ妞嶆ā鍨嬩腑锛孞6M0-mcMMAF锛? 鍜 4 mg/kg锛変笌瑁 J6M0 (2 mg/kg) 鐩告瘮琛ㄧ幇鍑烘洿涓哄己澶х殑鎶 MM 娲绘€с€傚讥婕€ SCID-beige MM 妯″瀷涓紝瑙傚療鍒 J6M0-mcMMAF锛?.4 鍜 4 mg/kg锛変笌 J6M0 (4 mg/kg) 鍜岃祴褰㈠墏鐩告瘮锛屼娇 MM 鑲跨槫蹇€熸秷闄ゅ苟寤堕暱浜嗙敓瀛樻湡銆侸6M0-mcMMAF 娌荤枟鍚庤瀵熷埌 MM 缁嗚優涓鍙戜簡鍚炲櫖浣滅敤锛圱ai, Y.-.T. et al. 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Bioorg Med Chem 2013, 21(24): 7724锛夈€ SUGLAT 鐗囧湪鏃ユ湰鑾锋壒娌荤枟 2 鍨嬬硸灏跨梾 Astellas Pharma 鍏徃鐨 Suglat(R)锛堜紛鏍煎垪鍑€ L-鑴皑閰革紝ipragliflozin L-proline锛?5- 鍜 50-mg 鐗囧墏娌荤枟 2 鍨嬬硸灏跨梾鍦ㄦ棩鏈幏寰椾笂甯傝鍙瘉銆傝鍏徃浜 2013 骞 3 鏈堢敵鎶ユ鎵瑰噯銆備紛鏍煎垪鍑€ L-鑴皑閰稿睘浜庨€夋嫨鎬ч挔/閽?钁¤悇绯栬浆杩愯泲鐧借川绫 2 (SGLT2) 鎶戝埗鍓傦紝鏄笌 Kotobuki Pharmaceutical 鍏徃閫氳繃绉戠爺鍚堜綔鍙戠幇鍜屽紑鍙戠殑銆傝鑽€氳繃閫夋嫨鎬ф姂 SGLT2 鑰屾姂鍒惰憽钀勭硸鍐嶆憚鍙栵紝浠庤€岄檷浣庤绯栥€備紛鏍煎垪鍑€ L-鑴皑閰稿崟鑽不鐤楃殑涓€椤 III 鏈熷叧閿€ц瘯楠岋紝浠ュ強璇ヨ嵂涓庡叾浠栭檷绯栬嵂鑱旂敤鐨勫椤逛复搴婄爺绌讹紝鏀寔浜嗘湰鍝佸湪鏃ユ湰鐨勮幏鎵广€侫stellas 鍏徃灏嗗埗閫犲拰閿€鍞骇鍝侊紝骞朵笌 Kotobuki Pharmaceutical 鍜 MSD K.K. 涓ゅ鍏徃鍏卞悓鎺ㄥ箍锛堣 2013 骞 9 鏈 3 鏃ャ€婃堡妫矾閫忚嵂鐗╂柊闂汇€嬶級锛圓stellas Pharma 鏂伴椈绋匡級銆灏忓垎瀛愰檷绯栬嵂鏂扮殑浣滅敤鏈哄埗瑙佹姤 Amgen 鍏徃鐮旂┒鑰呴壌瀹氬嚭灏忓垎瀛愯憽绯栨縺閰 (GK) 璋冭妭铔嬬櫧 (GCKR) 鎶戝埗鍓 AMG-1694 鍜 AMG-3969锛屼綔鐢ㄦ槸闄嶄綆钁¤悇绯栨按骞宠€屼笉浼氬鑷翠綆琛€绯栥€傛澶栵紝鏈枃浠嬬粛浜嗕汉浣 GCKR 涓師鍏堟湭閴村畾鐨勭粨鍚堣锛屼笉鍚屼簬涓庡北姊ㄩ唶-6-纾烽吀鐩愮粨鍚堝悗鎻愬崌 GK-GCKR 澶嶅悎浣撶ǔ瀹氭€х殑纾烽吀鏋滅硸缁撳悎浣嶇偣銆 GK 鍙皟鑺傝憽钀勭硸鍐呯ǔ鎬侊紝鍏惰嚜韬張鍙 GCKR 铔嬬櫧鐨勮皟鑺傦紝绌鸿吂鏃 GCKR 鍙縺娲 GK銆傞€嗚浆楂樿绯栫殑鍦ㄧ爺 GK 婵€娲诲墏鏄剧ず鍑哄鑷翠綆琛€绯栫殑涓嶈壇浣滅敤銆備絾閫氳繃鎶戝埗 GCKR 闂存帴澧炲姞 GK 娲绘€э紝鎴栧彲闃叉浣庤绯栫殑鍙戠敓銆傞壌瀹氬嚭鍩轰簬鍝屽棯鐨勫皬鍒嗗瓙寮烘晥 GCKR 鎶戝埗鍓 AMG-1694 鍜 AMG-3969銆侴CKR 浠ユ祿搴︿緷璧栨柟寮忔姂鍒朵簡 GK 娲绘€с€備絾鏈 GCKR 鏃讹紝AMG-1694 鎭㈠浜 GK 娲绘€э紝EC50 涓 0.02 mcM锛屼績杩涗簡 GK-GCKR 澶嶅悎鐗╃殑瑙ｇ锛圛C50 = 0.007 mcM锛夛紝澧炲姞浜 GK 鐨勫埄鐢ㄥ害銆傚北姊ㄩ唶-6-纾烽吀鐩愬湪棣栦釜绯栧紓鏋勯叾锛圫IS锛夊煙涓庣硸纾烽吀缁撳悎浣嶇偣缁撳悎浠ュ鍔犵ǔ瀹氭€э紝鑰屾櫠浣撶粨鏋勮В鏋愬拰鎴煭 GCKR 鍒嗘瀽琛ㄦ槑锛孉MG-1694 涓庨涓 SIS 鍩熷拰 N-绔殑涔嬮棿鐨勪竴涓嫭鐗瑰尯鍩熺粨鍚堜互绋冲畾澶嶅悎浣撱€備笌杩欎竴鏂板瀷浣嶇偣缁撳悎鍚庣牬鍧忎簡澶嶅悎浣撶ǔ瀹氭€х殑鏈哄埗灏氫笉娓呮銆傚湪澶ч紶鍘熶唬鑲濈粏鑳炰腑锛孉MG-1694 寮曞彂浜 GK 浠庣粏鑳炴牳鏄撲綅鍒拌優娴嗭紙IC50 = 0.065 mcM锛夛紝澧炲姞浜 2-鑴辨哀-D-钁＄硸纾烽吀锛圙K 娲诲寲鏍囪鐗╋級鐨勮搫绉紙EC50 = 0.053 mcM锛夈€傛甯稿ぇ榧犲拰 Zucker 绯栧翱鐥呰剛鑲ぇ榧犱腑锛孉MG-1694 浠ュ墏閲忎緷璧栨柟寮忎娇 GK 鏄撲綅姣旇憽钀勭硸鎴栨灉绯栨洿涓虹ǔ鍋ワ紝鑰屼笉浼氬奖鍝嶈娴嗚儼宀涚礌姘村钩銆傚湪琛€绯栨甯稿皬榧犱腑锛孉MG-1694 骞舵湭闄嶄綆琛€娴嗙硸钁¤悇绯栥€傜硸灏跨梾榧犳ā鍨嬩腑锛孉MG-3969 鏄庢樉闄嶄綆浜嗛珮琛€绯栵紙Lloyd, D.J. et al Nature 2013, 504(7480): 437锛夈€ 涓撳埄鏂囩尞涓粙缁嶄簡璇ュ寲鍚堢墿 (WO 2012027261)銆 TAXIS 鍏徃鎶ラ亾鍙ｆ湇鏉€鑿屽墠鑽殑寮€鍙戝拰涓村簥鍓嶇壒鐐 Taxis Pharmaceuticals 鍏徃鐮旂┒浜哄憳浠嬬粛浜 PC-190723 鍓嶈嵂 TXY-436 鍜 TXY-541 鐨勬椿浣撳唴鑽姩瀛︽€ц川锛孭C-190723 鍙牬鍧忕粏鑿岀粏鑳炲垎瑁傝泲鐧 FtsZ锛岃憽钀勭悆鑿屾劅鏌撻紶妯″瀷涓〃鐜板嚭寮哄ぇ鎶楄弻鐤楁晥銆鎰熸煋榧犳ā鍨嬬殑涓村簥鍓嶇爺绌惰〃鏄庤嫰鐢查叞鑳 PC-190723 鍏锋湁鎶楄弻鐤楁晥銆備絾 C-190723 鍙憾鎬у樊 (ClogP = 2.64)锛屼护鍏舵垚涓轰笉瀹滅敤浜庝汉浣撶殑鍊欓€夎嵂銆俆XY-436 鏄 PC-190723 鐨 N-鏇煎凹瑗跨⒈琛嶇敓鐗╋紝pH 涓 2.6 鏃跺叾鍙憾鎬 (ClogP = -0.51) 鏄瘝浣撳寲鍚堢墿鐨 100 鍊嶃€俻H 涓 7.4 鏃讹紝TXY-436 杞寲涓 PC-190723 鐨勫崐琛版湡鏄 18.2 +/鈥 1.6 鍒嗛挓銆俆XY-436 瀵瑰皬榧犺〃鐜板嚭鑹ソ鐨勫彛鏈嶇敓鐗╁埄鐢ㄥ害锛圥C-190723 鍓嶈嵂涓 33% 鍜 73%锛夛紝绋虫€佹椂鍒嗗竷瀹圭Н涓 5.77 L/kg銆俆XY-436 鍙婂悗缁 PC-190723 鐨勬秷闄ゅ崐琛版湡鍒嗗埆涓 0.26 鍜 0.96 灏忔椂銆俆XY-436 瀵硅憽钀勭悆鑿屽睘涓庢瘝鑽叿鏈夌浉浼肩殑鎶楄弻浣滅敤銆傚叏韬敳姘цタ鏋楁晱鎰熸垨鑰愯嵂鐨勯噾榛勮壊钁¤悇鐞冭弻鎰熸煋榧犳ā鍨嬩腑锛屽彛鏈 TXY-436 浣 67% 娌荤枟灏忛紶娑堥櫎浜嗕竴鑸細鑷存鐨勬劅鏌擄紝璇ヨ嵂瀵归潪娲茬豢鐚磋偩鑴忎笂鐨 Vero 缁嗚優浜︽棤姣掓€э紙Kaul, M. et al. Antimicrob Agents Chemother 2013, 57(12): 5860锛夈€ TXY-541 鏄 PC-190723 鐨 1-鐢插熀鍝屽暥-4-姘ㄧ敳閰板墠鑽紝鍦 10 mM 鏋告┘閰告恫 (pH 2.6) 涓殑鍙憾鎬ф槸姣嶈嵂鐨 143 鍊嶃€傜敓鐞嗘潯浠朵笅 (pH 7.4)锛孴XY-541 鍦ㄧ敓闀夸粙璐ㄤ腑杞寲涓 PC-190723 鐨勫崐琛版湡鏄 8.2 +/鈥 0.4 灏忔椂锛屼絾鍦ㄥ皬榧犺娓呬腑鐨勮浆鍖栭€熷害鏄 3.4 +/鈥 0.2 鍒嗛挓銆傚皬榧犺娓呬腑锛屾湰鍝佸钁¤悇鐞冭弻灞炰笌姣嶈嵂鍏锋湁鐩镐技鐨勬姉鑿屼綔鐢ㄣ€傚湪灏忛紶涓紝TXY-541-琛嶇敓 PC-190723 琛ㄧ幇鍑鸿壇濂界殑鍙ｆ湇鐢熺墿鍒╃敤搴 (29.6%)锛屽湪 15 鍒嗛挓鍐呰揪鍒拌娴嗗嘲娴撳害锛岀ǔ鎬佹椂鍒嗗竷瀹圭Н涓 2.18 L/kg銆俆XY-541 浜х墿 PC-190723 鐨勬秷闄ゅ崐琛版湡涓 0.6 灏忔椂銆傚墠鑽钁¤悇鐞冭弻灞炰笌姣嶈嵂鍏锋湁鐩镐技鐨勬姉鑿屼綔鐢ㄣ€傚彛鏈 TXY-436 娌荤枟浣 100% 鍏ㄨ韩閲戣憽鑿屾劅鏌撳皬榧犳秷闄や簡涓€鑸細鑷存鐨勬劅鏌撱€傛澶栵紝璇ヨ嵂瀵归潪娲茬豢鐚翠笂鐨 Vero 缁嗚優鏃犳瘨鎬э紙Kaul, M. et al Biochem Pharmacol 2013, 86(12): 1699锛夈€ 鍙戠幇鏂板瀷鍖栧悎鐗╂不鐤楀閲嶈€愯嵂缁撴牳鐥 Novartis 鍏徃鐨勭瀛﹀浠彂琛ㄤ簡涓ょ瘒鎶ラ亾锛屼粙缁嶄簡鍖栧悎鐗╁惒鍝?2-缇ч叞鑳猴紙NTD-219銆丯ITD-304 鍜 NITD-349锛夌殑璁捐銆佸悎鎴愬強涓村簥鍓嶇壒鐐癸紝鎷熺敤浜庡閲嶈€愯嵂缁撴牳鐥呯殑涓村簥娌荤枟銆傚鍒嗘灊鏉嗚弻鐨勮〃鍨嬬瓫鏌ラ壌鍒嚭鍚插摎-2-缇ч叞鑳烘槸涓€绉嶆綔鍦ㄦ姉缁撴牳鑽€傚鍏锋湁浜氭懇灏旀晥浠峰拰鍒嗘灊鏉嗚弻娲绘€х殑鍚插摎-2-缇ч叞鑳哄疄鏂戒簡缁撴瀯娲绘€у叧绯诲缓妯°€備慨楗板惒鍝氱幆鍜岀幆宸卞熀鍩哄洟浜х敓浜嗘椿浣撳鐮旂┒涓彈璇曠殑涓€绯诲垪鍖栧悎鐗┿€傝繖鏍锋鏌ュ浜轰綋缁嗚優鐨勭枟鏁堝拰缁嗚優姣掓€э紝鍦ㄦ椿浣撳唴璇曢獙涓骇鐢熶簡涓ょ鍏堝鍖栧悎鐗┿€侼ITD-304 鍜 NITD-349 琛ㄧ幇鍑鸿壇濂界殑姘存憾鎬у拰鑹ソ鐨勪唬璋㈢ǔ瀹氭€э紝MIC50 鍊煎垎鍒负 0.015 鍜 0.023 mcM銆傜敤鍙ｆ湇鎴栭潤鑴変娇鐢 25 鍜 5 mg/kg 鐨勫皬榧犺瘎浠蜂簡鑽姩瀛︺€備袱绉嶅寲鍚堢墿琛ㄧ幇鍑鸿緝浣庣殑鍏ㄨ韩娓呴櫎鐜囷紝涓埌楂樻按骞冲垎甯冨绉紝鍗婅“鏈熻寖鍥翠粙浜 4.5鈥? 灏忔椂锛屽彛鏈嶇敓鐗╁埄鐢ㄥ害浠嬩簬 51% 鈥 53%銆傛€ユ€х粨鏍哥梾鐨勯紶妯″瀷涓紝鍙ｆ湇 25 鍜 75 mg/kg NITD-304 鍒嗗埆浣胯偤鍏嬮殕褰㈡垚鍗曚綅鍑忓皯浜 2.6 鍜 4.8 涓鏁般€侼ITD-349 浣胯偤鍏嬮殕褰㈡垚鍗曚綅鍒嗗埆鍑忓皯 2.4 鍜 4.6 涓鏁帮紙Kondreddi, R.R. et al. J Med Chem 2013, 56(21): 8849锛夈€ NITD-304 鍜 NITD-349 瀵圭粨鏍稿垎鏋濇潌鑿 H37Rv 鐨勬晥浠锋槸寮傜儫鑲兼垨 PA-824鏄 10 鍊嶏紝鐤楁晥涓 TMC-207 鐩镐技銆備袱绉嶅寲鍚堢墿閮借〃鐜板嚭鏃堕棿鍜屾祿搴鈥渚濊禆鎬ф潃鑿屽姩鍔涘 (> 0.2 mcM)锛屽缂撴參鍜屽揩閫熺敓闀胯弻鏍湁鏁堬紝浣嗗涓嶅鍒剁殑瀹垮瓨鑿屾牚鏃犳晥銆侼ITD-219銆丯ITD-304 鍜 NITD-349锛?lt; 0.04 鈥 0.08 mcM锛夊缁撴牳鍒嗘灊鏉嗚弻澶氶噸鑰愯嵂鑿屾牚琛ㄧ幇鍑鸿嵂鏁堛€傞紶绫汇€佸暜榻垮姩鐗╁拰鐘被妯″瀷涓紝NITD-304 鍜 NITD-349 琛ㄧ幇鍑烘湁鍒╃殑鑽姩瀛︼紝娑堥櫎鍗婅“鏈熼暱锛屽彛鏈嶇敓鐗╁埄鐢ㄥ害楂橈紝琛€娴嗘毚闇查噺姘村钩瓒呰繃娲讳綋澶栬嵂鏁堟墍闇€姘村钩銆傞紶绫绘劅鏌撴ā鍨嬩腑锛孨ITD-304 鍜 NITD-349 娌荤枟 2 鍛ㄥ悗鐨勭枟鏁堜笌鍒╃骞崇浉杩戯紝浼樹簬涔欒兒涓侀唶銆傝繖浜涘寲鍚堢墿鏃犲壇浣滅敤锛屽彲鑹ソ鑰愬彈銆傜幇宸茶〃鏄庤繖浜涘寲鍚堢墿閫氳繃闃绘柇闇夎弻閰搁叝绮橀檮鍒扮粏鑳炲涓婏紝浠庤€屽彂鎸ョ粏鑿岀粏鑳炲鐢熺墿鍚堟垚鎶戝埗鍓傜殑浣滅敤锛圧ao, S.P.S. et al. Sci Transl Med 2013, 5(214): 1锛夈€ AIC-649 鐢ㄤ簬鎱㈡€х梾姣掓€ф劅鏌撴不鐤楁柊绛栫暐鐨勪复搴婂墠寮€鍙鍦ㄥ濞佸し鐨 HEP DART浼氳涓婏紝AiCuris 鍏徃鎶ュ憡浜嗕竴绉嶅埡婵€瀵规寔缁€х梾姣掓劅鏌擄紙鍖呮嫭涔欏瀷鑲濈値鐥呮瘨锛孒BV锛夊仛鍑哄厤鐤簲绛旂殑鏂版柟娉曘€ 杩欎竴绛栫暐涓娇鐢ㄤ簡鐏椿鍓棙鐥呮瘨棰楃矑鍒跺墏 AIC-649 鍒烘縺鍏嶇柅搴旂瓟銆傜幇鍦ㄥ凡鐭ュ壇鐥樼梾姣掑叿鏈夐潪鐗瑰紓鎬с€佸箍璋卞厤鐤埡婵€娲绘€с€傚皬榧犵粡闈欒剦缁欎簣鍗曞墏閲 AIC-649 鍒烘縺浜嗙粏鑳炲洜瀛愮殑閲婃斁锛屽寘鎷共鎵扮礌纬鍜伪銆乀NF-伪銆佸崟鏍哥粏鑳炶秼鍖栬泲鐧 1 (MCP-1) 鍙婄櫧浠嬬礌-6 (IL-6)銆傛澶栵紝鍦ㄨ浆鍩哄洜灏忛紶妯″瀷涓紝AIC-649 闄嶄綆 HBV 鐥呮瘨杞介噺鐨勪綔鐢ㄤ笌娉拌绂忛煢鐩镐豢銆備娇鐢ㄨ繖涓€绛栫暐鐨勬洿澶氳瘉鎹潵鑷浛浠 HBV 鐨勬棻鐛倽鐐庣梾姣 (WHV)銆傛劅鏌撴棻鐛娇鐢 AIC-649 鍚庯紝WHV 琛ㄩ潰鎶楀師姘村钩鏄庢樉闄嶄綆銆傛湰鐮旂┒涓烘參鎬ф劅鏌撹儗鏅笅浣跨敤杩欎竴璇曢獙鎬ф不鐤楃殑鍏嶇柅鍒烘縺娲绘€ф彁渚涗簡姒傚康楠岃瘉銆傝繖涓€娌荤枟鏈夊笇鏈涗笌鎶楃梾姣掕嵂鑱斿悎浣跨敤鏀瑰杽瀹夸富鍏嶇柅搴旂瓟锛岀洰鍓嶆鍦ㄨ繘鍏 I 鏈熶复搴婅瘯楠屻€傛嵁鎺ㄦ祴锛孉IC-649 浣滅敤浜庢姉鐥呮瘨淇″彿浼犻€掗€氳矾鐨勬瀬鏃╅樁娈碉紝鍙兘鏄€氳繃鍒烘縺鎶楀師鍛堥€掔粏鑳炴縺娲 T 缁嗚優銆傛澶栬繕鎻愮ず杩欎竴閫斿緞閽堝鍏朵粬鎱㈡€х梾姣掓€ф劅鏌撳彲鑳戒篃鏈夊箍娉涗綔鐢紝濡傚崟绾柋鐤圭梾姣 (HSV) 鎴 HIV銆傚湪涓€涓尶鐚村厤鐤己闄风梾姣 (SIV) 妯″瀷涓紝鎶楅€嗚浆褰曠梾姣掔枟娉曡仈鍚 AIC-649 浣垮緱 CD4 缁嗚優澧炲鍜岀敓瀛樻湡寤堕暱锛圥aulsen, D. et al. HEP DART (Dec 8-12, Kohala Coast, Hawaii) 2013, Abst 111锛夈€ 鍙戠幇娌荤枟鐤熺柧鐨勬柊铔嬬櫧闈舵爣鍜屾柊鍨嬪寲鍚堢墿鍥界珛鍗敓鐮旂┒闄 (NIH) 璧勫姪鐨勪竴涓爺绌跺洟闃熷彂鐜颁簡纾疯剛閰拌倢閱 4-OH 婵€閰 (PI4K) III 鍨尾 (PI4KIIIbeta)锛岃繖绉嶈泲鐧借川鏄枱鍘熻櫕灞炵敓鍛藉懆鏈熸墍鏈夐樁娈甸兘閮藉繀椤荤殑銆傛澶栵紝浠栦滑鎶ラ亾鍙戠幇浜嗕竴绫绘柊鐨勫寲鍚堢墿鍜攽骞跺悺鍡紙imidazopyrazine锛夊寲鍚堢墿锛堝寘鎷琄AI-407銆並DU-691 鍜 KAI-715锛夊強涓€绉嶅柟鍣佸晧 BQR-695锛岄拡瀵瑰苟鍙姂鍒惰繖绉嶈泲鐧借川锛屽皢鎴愪负娌荤枟鐤熺柧鐨勪竴鎵规柊鑽€ 鐜版湁鐨勬姉鐤熻嵂閽堝鐨勬槸鎼哄甫鐤熺柧鐨勫瘎鐢熻櫕锛屽彧鑳介拡瀵瑰彂鑲蹭腑鐨勬煇涓樁娈点€傞拡瀵瑰瘎鐢熻櫕鐢熷懡鍛ㄦ湡鎵€鏈夐樁娈电殑鑽墿鏄汉浠ⅵ瀵愪互姹傜殑銆備竴绉嶅熀浜庣粏鑳炵殑鎭舵€х枱鍘熻櫕绛涙煡鎻ず浜嗕竴绫绘柊鐨勫挭鍞戝苟鍚″棯鎶楃枱鑽紝瀵瑰嚑绉嶈€愯嵂瀵勭敓铏搧绯绘湁鏁堛€傚熀浜庣粏鑳炵殑妫€鏌ヤ腑锛孠AI-407銆並DU-691 鍜 KAI-715 鍧囧鍟娇鍔ㄧ墿瀵勭敓铏害姘忕枱鍘熻櫕鍦ㄨ倽鑴忛樁娈电殑鍙戣偛鏈夋晥銆侹DU-691 鍦ㄥ皬榧犳椿浣撳唴闃叉浜嗕集姘忕枱鍘熻櫕鎰熸煋鎵€鑷存浜°€傛澶栵紝KDU-691 鍒氬湪鑲濊剰鍙戠敓闃舵涔嬪悗灏辨秷鐏簡瀵勭敓铏€備綆鍓傞噺鏃惰繕瀵圭尨鐤熷師铏畾灞呰倽鑴忎紤鐪犲瓙鏈夋晥锛圛C50 = 196 nM锛夛紝瀵逛汉闂存棩鐤熷師铏 (IC50 = 69 nM) 鍜屾伓鎬х枱鍘熻櫕 (IC50 = 118 nM) 琛€娑叉湡浼戠湢瀛愪篃鏈夋晥銆侹DU-691 鑳戒互鍓傞噺渚濊禆鏂瑰紡锛屽己鍔涢檷浣庨厤瀛愭瘝缁嗚優娲诲姏 (IC50 = 220 nM)锛岄樆鏂叾浼犳挱缁欒殜瀛 (IC50 = 316 nM)銆傝瀵熷埌 KAI-407 娌荤枟鎶戝埗浜嗙孩缁嗚優鍐呭懆鏈熷唴鏋佹櫄鏈熺殑琛€娑查樁娈佃優璐ㄥ垎瑁傦紝鍙戠幇鏄敱璐ㄨ啘鍐呯Щ鎵€鑷淬€傚 KAI-407 鑰愯嵂鎭舵€х枱鍘熻櫕鐨勯仐浼犵瓫鏌ラ壌鍒嚭瀵勭敓铏剛鑲縺閰秔fpi4k 绐佸彉锛屾彁绀虹壒鏄挭鍞戝苟鍚″棯绫诲箍娉涚壒寮傛€х殑娼滃湪闈舵爣銆侭QR-695 灞炰簬鍠瑰檨鍟夛紝閽堝鐨勪篃鏄 PI4KIIIbeta锛屽 KAI-407 鑰愯嵂鎭舵€х枱鍘熻櫕鍚屾牱鏃犳晥銆傚鑰愯嵂瀵勭敓铏殑閬椾紶鏀归€犺鍙戜簡瀵 KAI-407 鐨勬晱鎰熸€э紝璇佸疄 PI4KIIIbeta 鏄竴涓柊鍨嬫姉鐤熻嵂鐗╅澏鏍 (McNamara, C.W. et al. Nature 2013, 504(7479): 248)銆 TORII 鍏徃鑸屼笅鍏嶇柅娌荤枟鑽不鐤楁棩鏈鏌忚姳绮夊湪鏃ユ湰鑾锋壒 Torii Pharmaceutical 鍏徃鐨 Cedartolen(R) 鑸屼笅婊村墏鈥撴棩鏈鏌忚姳绮夊湪鏃ユ湰鑾峰緱鎵瑰噯锛岃繖绉嶈垖涓嬪厤鐤不鐤楄嵂娌荤殑閫傚簲鐥囨槸鏃ユ湰棣欐煆鑺辩矇鐑€傛敮鎸佸叾鑾锋壒鐨勬槸鏃ユ湰棣欐煆鑺辩矇鐑偅鑰呯殑涓€椤 III 鏈熸棩鏈爺绌讹紝璇ョ爺绌惰揪鍒颁簡鍏朵富瑕佺枟鏁堢粓鐐癸紝琛ㄦ槑 Cedartolen 娌荤枟缁撴潫鏃跺鍑忚交鎬讳綋榧昏厰鐥囩姸鍙婇檷浣庣敤鑽瘎鍒嗘槑鏄句紭浜庡畨鎱板墏锛屽叿鏈夌粺璁″鎰忎箟锛堣 2012 骞 9 鏈 17 鏃ャ€婃堡妫矾閫忚嵂鐗╂柊闂汇€嬶級銆傛鑽兘鍦ㄥ浣跨敤锛岃璁＄洰鐨勬槸鍙栦唬鐨笅娉ㄥ皠锛圱orii Pharmaceutical 鏂伴椈绋匡級銆侟/p> </div> <div id="copy">浣滆€咃細涓嶈銆€鏉ユ簮锛氭堡濮嗘．璺€廃/div> <div class="sxart"> <li>涓婁竴绡囷細<a href="List.asp?ID=1312">姣忔湀鑽墿蹇 -2014骞?鏈圏/a></li><li>涓嬩竴绡囷細<a href="List.asp?ID=1422">2016涓編娆ц嵂鐗╁鎵瑰崐骞存姤</a></li> </div> </div> <div id="web2l"> <h6>鐩稿叧鏂囩珷</h6> <div id="marticle"> <ul> <li>路<a href="/List.asp?ID=339">鑱旂郴鎴戜滑</a></li> <li>路<a href="/List.asp?ID=284">鑽墿闈炰复搴婅瘎浠风爺绌朵腑蹇傸br>锛堝浗瀹跺箍宸炴柊鑽畨鍏ㄨ瘎浠风爺绌堕噸鐐瑰疄楠屽锛堻/a></li> <li>路<a href="/List.asp?ID=274">骞胯嵂鎬婚櫌鏈夐檺鍏徃鐜颁换棰嗗</a></li> <li>路<a href="/List.asp?ID=1">骞胯嵂鎬婚櫌鏈夐檺鍏徃绠€浠婞/a></li> <li>路<a 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