Bcl-X_L蛋白拮抗剂分子设计的研究进展
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摘要
Bcl-X_L是Bcl-2家族蛋白重要的成员之一。作为细胞凋亡的关键效应因子,已成为目前最具吸引力的癌症治疗靶点之一。在介绍Bcl-2家族蛋白调控细胞凋亡机制的基础上,对近5年报道的新型Bcl-X_L蛋白拮抗剂的分子设计历程进行综述,着重阐述基于全新药物设计方法、高通量筛选、X线单晶衍射技术、计算机辅助药物设计以及衍生化修饰设计出的3类结构新颖、活性显著和靶向性优良的小分子肽模拟物。研究表明:苯甲酰脲类对Bcl-X_L蛋白具有极强的靶向性;磺酰胺类对Bcl-X_L蛋白的抑制活性可以达到纳摩尔水平;苯并噻唑类具有极佳的生物利用度。这3类分子骨架的设计代表了现代抗癌药物分子设计中三大发展方向,该研究将会对未来抗癌药物的研发提供借鉴,同时还对3类化合物作为Bcl-X_L蛋白拮抗剂的发展进行了展望。
Bcl-X_Lis one of the most important members of the Bcl-2 family protein,and a most attractive therapeutic target for cancer. Here,we review the molecular design of novel Bcl-X_Lprotein antagonists reported in the recent five years and the role of Bcl-2 family protein in apoptosis mechanism.Three novel small molecule peptides mimetic with novel activities and significant selectivity are designed based on the de novo drug design,high-throughput screening,X-ray diffraction crystallography,computer-aided drug design and receptor-based derivatization modification. Among them,benzoylurea has strong selectivity for Bcl-X_Lprotein; the inhibitory activity of sulfonamides on Bcl-X_Lprotein can reach the nanomolar level;benzothiazoles have excellent bioavailability. The design of the molecular skeleton represents the three major directions in the design of modern pharmaceutical molecules. Finally,we also indicate future development of these three kinds of compounds as antagonists of Bcl-X_Lprotein.
Bcl-X_Lis one of the most important members of the Bcl-2 family protein,and a most attractive therapeutic target for cancer. Here,we review the molecular design of novel Bcl-X_Lprotein antagonists reported in the recent five years and the role of Bcl-2 family protein in apoptosis mechanism.Three novel small molecule peptides mimetic with novel activities and significant selectivity are designed based on the de novo drug design,high-throughput screening,X-ray diffraction crystallography,computer-aided drug design and receptor-based derivatization modification. Among them,benzoylurea has strong selectivity for Bcl-X_Lprotein; the inhibitory activity of sulfonamides on Bcl-X_Lprotein can reach the nanomolar level;benzothiazoles have excellent bioavailability. The design of the molecular skeleton represents the three major directions in the design of modern pharmaceutical molecules. Finally,we also indicate future development of these three kinds of compounds as antagonists of Bcl-X_Lprotein.
引文
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[31] ZHOU H,AGUILAR A,CHEN J,et al.Structure-based design of potent Bcl-2/Bcl-XLinhibitors with strong in vivo antitumor activity[J].J Med Chem,2012,55(13):6149-6161.
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[33] AGUILAR A,ZHOU H,CHEN J,et al. A potent and highly efficacious Bcl-2/Bcl-XLinhibitor[J]. J Med Chem,2013,56(7):3048-3067.
[34] SLEEBS B E,KERSTEN W J,KULASEGARAM S,et al.Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL[J]. J Med Chem,2013,56(13):5514-5540.
[35] TAO Z F,HASVOLD L,WANG L,et al.Discovery of a potent and selective Bcl-XLinhibitor with in vivo activity[J]. ACS Med Chem Lett,2014,5(10):1088-1093.
[36] KOEHLER M F T,BERGERON P,CHOO E F,et al.Structureguided rescaffolding of selective antagonistsof BCL-XL[J].ACS Med Chem Lett,2014,5(6):662-667.
[2] OLTERSDORF T,ELMORE S W,SHOEMAKER A R,et al.An inhibitor of Bcl-2 family proteins induces regression of solid tumors[J].Nature,2005,435:677-681.
[3]孟菁菁,黄大毛,唐发清.蛋白质与蛋白质相互作用的研究进展[J].临床与病理杂志,2008,28(6):471-476.
[4]朱雄增,李小秋.解读2008年恶性淋巴瘤WHO分类:T细胞和NK细胞淋巴瘤[J].临床与实验病理学杂志,2010,26(4):385-388.
[5] LLAMBI F,D R GREEN. Apoptosis and oncogenesis:give and take in the Bcl-2 family[J]. Curr Opin Genet Dev,2011,21(1):12-20.
[6] AKL H,VERVLOESSEM T,KIVILUOTO S,et al.A dual role for the anti-apoptotic Bcl-2 protein in cancer:mitochondria versus endoplasmic reticulum[J]. Biochim Biophys Acta,2014,1843(10):2240.
[7] LETAI A,BASSIK M C,WALENSKY L D,et al. Distinct BH3domains either sensitize or activate mitochondrial apoptosis,serving as prototype cancer therapeutics[J].Cancer Cell,2002,2(3):183-192.
[8] SAROSIEK K A,CHI X,BACHMAN J A,et al.Bid preferentially activates Bak while Bim preferentially activates Bax,affecting chemotherapy response[J].Mol Cell,2013,51(6):751-765.
[9] TAIT S W,GREEN D R. Mitochondria and cell death:outer membrane permeabilization and beyond[J]. Nat Rev Mol Cell Biol,2010,11(9):621-632.
[10] CHIPUK J E,GREEN D R. How do Bcl-2 proteins induce mitochondrial outer membrane permeabilization?[J]. Trends Cell Biol,2008,18(14):157-164.
[11] ZAMAN S,WANG R,GANDHI V. Targeting the apoptosis pathway in hematologic malignancies[J]. Leuk Lymphom,2014,55(9):1980-1992.
[12] RENAULT T T,CHIPUK J E. Death upon a kiss:mitochondrial outer membrane composition and organelle communication govern sensitivity to Bak/Bax-dependent apoptosis[J]. Chem Biol,2014,21(1):114-123.
[13] DOSHI J M,TIAN D,XING C,et al.Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate(HA 14-1),an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer[J].J Med Chem,2006,49(26):7731-7739.
[14] PAILLARD A,HINDREF,VIGNES-COLOMBEIX C,et al.The importance of endo-lysosomal escape with lipid nanocapsules for drug subcellular bioavailability[J]. Biomaterials,2010,31(29):7542-7554.
[15] WEYLAND M,MANERO F,PAILLARD A,et al. Mitochondrial targeting by use of lipid nanocapsules loaded with SV30,an analogue of the small-molecule Bcl-2 inhibitor HA14-1[J]. J Control Release,2011,151(1):74-82.
[16] GREE D,VORIN S,MANTHATI V L,et al.The synthesis of new,selected analogues of the pro-apoptotic and anticancer molecule HA 14-1[J].Tetrahedron Lett,2008,49(20):3276-3278.
[17] BRADY R M,VOM A,ROY M J,et al.De-novo designed library of benzoylureas as inhibitors of Bcl-XL:synthesis,structural and biochemical characterization[J].J Med Chem,2014,57(4):1323-1343.
[18] BAELL J B,DUGGAN P J,FORSYTH S A,et al.Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics ofω-conotoxin GVIA[J]. Tetrahedron,2006,62(31):7284-7292.
[19] SLEEBS B E,KERSTEN W J,KULASEGARAM S,et al.Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL[J].J Med Chem,2013,56(13):5514.
[20] BRADY R M,HATZIS E,CONNOR T,et al. Synthesis of conformationally constrained benzoylureas as BH3-mimetics[J].Org Biomol Chem,2012,10(27):5230-5237.
[21] BRADY R M,KHAKHAM Y,LESSENE G,et al. Cheminform abstract:benzoylureas as removable cis amide inducers:synthesis of cyclic amides via ring closing metathesis(RCM)[J].Cheminform,2011,9(3):656-658.
[22] RODRIGUEZ J M,ROSS N T,KATT W P,et al. Structure and function of benzoylurea-derivedα-helix mimetics targeting the Bcl-XL/Bak binding interface[J]. Chem Med Chem,2009,4(4):649-656.
[23] LESSENE G,CZABOTAR P E,SLEEBS B E,et al. Structureguided design of a selective BCL-XLinhibitor[J]. Nat Chem Biol,2013,9(6):390-397.
[24] LEE E F,CZABOTAR P E,SMITH B J,et al.Crystal structure of ABT-737 complexed with Bcl-XL:implications for selectivity of antagonists of the Bcl-2 family[J]. Cell Death Differ,2007,14(9):1711-1713.
[25] OLARU A,BALA C,JAFFREZICRENAULT N,et al. Surface plasmon resonance(SPR)biosensors in pharmaceutical analysis[J].Crit Rev Anal Chem,2015,45(2):97-105.
[26] LOCK R,CAROL H,HOUGHTON P J,et al.Initial testing(stage 1)of the BH3 mimetic ABT-263 by the pediatric preclinical testing program[J].Pediatric Blood Cancer,2008,50(6):1181-1189.
[27] CANG S,IRAGAVARAPU C,SAVOOJI J,et al. ABT-199(venetoclax)and BCL-2 inhibitors in clinical development[J].J Hematoloncol,2015,8(1):129.
[28] CZABOTAR P E,LESSENE G,STRASSER A,et al. Control of apoptosis by the Bcl-2 protein family:implications for physiology and therapy[J].Nat Rev Mol Cell Biol,2014,15(1):49-63.
[29] SOUERS A J,LEVERSON J D,BOGHAERT E R,et al,ABT-199,a potent and selective Bcl-2 inhibitor,achieves antitumor activity while sparing platelets[J]. Nat Med,2013,19(2):202-208.
[30] SLEEBS B E,CZABOTAR P E,FAIRBROTHER W J,et al.Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity[J].J Med Chem,2011,54(6):1914-1926.
[31] ZHOU H,AGUILAR A,CHEN J,et al.Structure-based design of potent Bcl-2/Bcl-XLinhibitors with strong in vivo antitumor activity[J].J Med Chem,2012,55(13):6149-6161.
[32] ZHOU H,CHEN J,MEAGHER J L,et al.Design of Bcl-2 and Bcl-XLinhibitors with subnanomolar binding affinities based upon a new scaffold[J]. J Med Chem,2012,55(10):4664-4682.
[33] AGUILAR A,ZHOU H,CHEN J,et al. A potent and highly efficacious Bcl-2/Bcl-XLinhibitor[J]. J Med Chem,2013,56(7):3048-3067.
[34] SLEEBS B E,KERSTEN W J,KULASEGARAM S,et al.Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL[J]. J Med Chem,2013,56(13):5514-5540.
[35] TAO Z F,HASVOLD L,WANG L,et al.Discovery of a potent and selective Bcl-XLinhibitor with in vivo activity[J]. ACS Med Chem Lett,2014,5(10):1088-1093.
[36] KOEHLER M F T,BERGERON P,CHOO E F,et al.Structureguided rescaffolding of selective antagonistsof BCL-XL[J].ACS Med Chem Lett,2014,5(6):662-667.