抗凋亡蛋白Mcl-1及其抑制剂的研究进展
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摘要
骨髓细胞白血病蛋白Mcl-1是Bcl-2家族蛋白中重要的抗凋亡蛋白成员,其在多种恶性肿瘤(急性细胞性白血病、多发性骨髓瘤等)中都具有高表达的特点,导致肿瘤细胞对传统化疗药物及Bcl-2抑制剂产生耐药性。Mcl-1作为抗肿瘤药物研发的重要靶点正日益受到相关研究人员的关注,其中Mcl-1新型抑制剂以及联合抑制剂的研究取得了较大进展。本文将对Mcl-1蛋白结构和功能以及相关抑制剂的研究做更深入的分析和总结。
Bone marrow cell leukemia protein Mcl-1 is an important member of the anti-apoptotic protein in the Bcl-2 family protein, and has high expression in many kinds of malignant tumor(acute cell leukemia, multiple myeloma, etc), resulting in drug resistance to traditional chemotherapeutic agents and Bcl-2 inhibitors. As an important target for the research and development of antitumor drugs, Mcl-1 is increasingly concerned by the researchers. Great progress has been made in the research of new Mcl-1 inhibitors and joint inhibitors. This article will make a more in-depth analysis of the structure and function of Mcl-1 protein and related inhibitors, and results of the study will be of great significance for the treatment of cancer.
Bone marrow cell leukemia protein Mcl-1 is an important member of the anti-apoptotic protein in the Bcl-2 family protein, and has high expression in many kinds of malignant tumor(acute cell leukemia, multiple myeloma, etc), resulting in drug resistance to traditional chemotherapeutic agents and Bcl-2 inhibitors. As an important target for the research and development of antitumor drugs, Mcl-1 is increasingly concerned by the researchers. Great progress has been made in the research of new Mcl-1 inhibitors and joint inhibitors. This article will make a more in-depth analysis of the structure and function of Mcl-1 protein and related inhibitors, and results of the study will be of great significance for the treatment of cancer.
引文
[1] Hassan M, Watari H, Abualmaaty A, et al. Apoptosis and molecular targeting therapy in cancer[J]. Biomed Research International, 2014,2014(2):150845
[2] Eisele G, Weller M. Targeting apoptosis pathways in glioblastoma[J].Cancer Letters, 2013, 332(2):335-345
[3] Levy M, Claxton D. Therapeutic inhibition of BCL-2 and related family members[J]. Expert Opinion on Investigational Drugs, 2017,26(3):293-301
[4] Delbridge A R, Grabow S, Strasser A, et al. Thirty years of BCL-2:translating cell death discoveries into novel cancer therapies[J].Nature Reviews Cancer, 2016, 16(2):99-109
[5] Zheng J H, Viacava F A, Kriwacki R W, et al. Discoveries and controversies in BCL-2 protein-mediated apoptosis[J]. Febs Journal,2016, 283(14):2690-2700
[6] Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors[J]. Aging Cell, 2016, 15(3):428-435
[7] Belmar J, Fesik S W. Small molecule Mcl-1 inhibitors for the treatment of cancer[J]. Pharmacology&Therapeutics, 2015, 145:76-84
[8] Oltersdorf T, Elmore S W, Shoemaker A R, et al. An inhibitor of Bcl-2family proteins induces regression of solid tumours[J]. Nature, 2005,435(7042):677-681
[9] Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia[J]. Cancer Cell, 2006, 10(5):375-388
[10] Tahir S K, Yang X, Anderson M G, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737[J]. Cancer Research, 2007, 67(3):1176-1183
[11] Petros A M, Nettesheim D G, Wang Y, et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis,and biophysical studies[J]. Protein Science a Publication of the Protein Society, 2000, 9(12):2528-2534
[12] Czabotar P E, Lee E F, Van M D, et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007,104(15):6217-6222
[13] Lee E F, Czabotar P E, van Delft M F, et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation[J]. Journal of Cell Biology, 2008, 180(2):341-355
[14] Liu Q, Moldoveanu T, Sprules T, et al. Apoptotic regulation by MCL-1 through heterodimer ization[J]. Journal of Biological Chemistry, 2010, 285(25):19615-19624
[15] Kim J H, Bae J. MCL-1ES induces MCL-1L-dependent BAX-and BAK-independent mitochondrial apoptosis[J]. Plos One, 2013, 8(11):e79626
[16] Giampaolo M, Carlotta G, Dario B, et al. Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death[J].Molecular Biology of the Cell, 2015, 27(1):20-34
[17] Tian D, Das S G, Doshi J M, et al. SHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell[J].Cancer Letters, 2008, 259(2):198-208
[18] Tzung S P, Kim K M, Basa觡ez G, et al. Antimycin a mimics a cell-death-inducing Bcl-2 homology domain 3[J]. Nature Cell Biology, 2001, 3(2):183-191
[19] Chen L, Fletcher S. Mcl-1 inhibitors:A patent review[J]. Expert Opinion on Therapeutic Patents, 2016, 27(2):163-178
[20] Thomas L W, Lam C, Edwards S W. Mcl-1:the molecular regulation of protein function[J]. Febs Letters, 2010, 584(14):2981-2989
[21] Schwartz P S, Manion M K, Emerson C B, et al. 2-Methoxy antimycin reveals a unique mechanism for Bcl-x(L)inhibition[J].Molecular Cancer Therapeutics, 2007, 6(7):2073-2080
[22] Vela L, Marzo I. Bcl-2 family of proteins as drug targets for cancer chemotherapy:the long way of BH3 mimetics from bench to bedside[J]. Current Opinion in Pharmacology, 2015, 23:74-81
[23] Goodwin C M, Rossanese O W, Olejniczak E T, et al. Myeloid cell leukemia-1 is an important apoptotic survival factor in triple-negative breast cancer[J]. Cell Death&Differentiation, 2015, 22(12):2098-2106
[24] Quinn B A, Dash R, Azab B, et al. Targeting Mcl-1 for the therapy of cancer[J]. Expert Opinion on Investigational Drugs, 2011, 20(10):1397-1411
[25] Xu G, Liu T, Zhou Y, et al. 1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors:design, synthesis, and preliminary biological evaluation[J]. Bioorganic&Medicinal Chemistry, 2017, 25(20):5548-5556
[26] Qiao Z, Wang J, Wang H, et al. Inhibition of breast cancer cell proliferation by a newly developed photosensitizer chrolophyll derivative CPD4[J]. International Journal of Clinical&Experimental Medicine, 2014, 8(5):7381-7387
[27] Woo S M, Min K J, Bo R S, et al. YM155 enhances ABT-737-mediated apoptosis through Mcl-1 down regulation in Mcl-1-overexpressed cancer cells[J]. Molecular&Cellular Biochemistry,2017, 429(2):91-102
[28] Yu X, Wei L, Xia Z, et al. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis[J]. Bmc Cancer, 2017, 17(1):449
[29] Varadarajan S, Vogler M, Butterworth M, et al. Evaluation and critical assessment of putative MCL-1 inhibitors[J]. Cell Death&Differentiation, 2013, 20(11):1475-1484
[30] Zhao M Y, Chen H Y, Liu Y, et al. MiR-29 modulates multidrug resistance of gastric cancer cells by targeting Mcl-1[J]. World Chinese Journal of Digestology, 2016, 24(36):4781
[31] Pan R, Ruvolo V R, Wei J, et al. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor(-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia[J]. Blood, 2015, 126(3):363-372
[32] Kotschy A, Szlavik Z, Murray J, et al. The MCL-1 inhibitor S63845is tolerable and effective in diverse cancer models[J]. Nature, 2016,538(7626):477-482
[33] Letai A. S63845, an MCL-1 selective BH3 mimetic:another arrow in our quiver[J]. Cancer Cell, 2016, 30(6):834-835
[34] Merino D, Whittle J R, Vaillant F, et al. Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer[J]. Science Translational Medicine, 2017, 9(401)
[35] Bruncko M, Wang L, Sheppard GS, et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity[J].Journal of Medicinal Chemistry, 2015, 58(5):2180-2194
[36] Leverson J D, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263(navitoclax)[J]. Cell Death&Disease, 2015, 6(1):e1590
[37] DA Luedtke, Yubin Ge, Xiaojia Niu, et al. Inhibition of Mcl-1enhances cell death induced by the Bcl-2-selective inhibitor ABT-199in acute myeloid leukemia cells[J]. Signal Transduction and Targeted Therapy, 2017, 7(23):34785-34799
[38] Besbes S, Pocard M, Mirshahi M, et al. The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia[J]. Critical Reviews in Oncology/hematology, 2016, 100(1):32-36
[39] Liu T, Wan Y, Liu R, et al. Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors[J]. Bioorg Med Chem, 2017, 25(6):1939-1948
[40] Hird A W, Secrist J P, Adam A, et al. Abstract DDT01-02:AZD5991:A potent and selective macrocyclic inhibitor of Mcl-1 for treatment of hematologic cancer[J]. Cancer Research, 2017, 77(13Supplement):DDT01-02-DDT01-02
[2] Eisele G, Weller M. Targeting apoptosis pathways in glioblastoma[J].Cancer Letters, 2013, 332(2):335-345
[3] Levy M, Claxton D. Therapeutic inhibition of BCL-2 and related family members[J]. Expert Opinion on Investigational Drugs, 2017,26(3):293-301
[4] Delbridge A R, Grabow S, Strasser A, et al. Thirty years of BCL-2:translating cell death discoveries into novel cancer therapies[J].Nature Reviews Cancer, 2016, 16(2):99-109
[5] Zheng J H, Viacava F A, Kriwacki R W, et al. Discoveries and controversies in BCL-2 protein-mediated apoptosis[J]. Febs Journal,2016, 283(14):2690-2700
[6] Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors[J]. Aging Cell, 2016, 15(3):428-435
[7] Belmar J, Fesik S W. Small molecule Mcl-1 inhibitors for the treatment of cancer[J]. Pharmacology&Therapeutics, 2015, 145:76-84
[8] Oltersdorf T, Elmore S W, Shoemaker A R, et al. An inhibitor of Bcl-2family proteins induces regression of solid tumours[J]. Nature, 2005,435(7042):677-681
[9] Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia[J]. Cancer Cell, 2006, 10(5):375-388
[10] Tahir S K, Yang X, Anderson M G, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737[J]. Cancer Research, 2007, 67(3):1176-1183
[11] Petros A M, Nettesheim D G, Wang Y, et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis,and biophysical studies[J]. Protein Science a Publication of the Protein Society, 2000, 9(12):2528-2534
[12] Czabotar P E, Lee E F, Van M D, et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007,104(15):6217-6222
[13] Lee E F, Czabotar P E, van Delft M F, et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation[J]. Journal of Cell Biology, 2008, 180(2):341-355
[14] Liu Q, Moldoveanu T, Sprules T, et al. Apoptotic regulation by MCL-1 through heterodimer ization[J]. Journal of Biological Chemistry, 2010, 285(25):19615-19624
[15] Kim J H, Bae J. MCL-1ES induces MCL-1L-dependent BAX-and BAK-independent mitochondrial apoptosis[J]. Plos One, 2013, 8(11):e79626
[16] Giampaolo M, Carlotta G, Dario B, et al. Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death[J].Molecular Biology of the Cell, 2015, 27(1):20-34
[17] Tian D, Das S G, Doshi J M, et al. SHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell[J].Cancer Letters, 2008, 259(2):198-208
[18] Tzung S P, Kim K M, Basa觡ez G, et al. Antimycin a mimics a cell-death-inducing Bcl-2 homology domain 3[J]. Nature Cell Biology, 2001, 3(2):183-191
[19] Chen L, Fletcher S. Mcl-1 inhibitors:A patent review[J]. Expert Opinion on Therapeutic Patents, 2016, 27(2):163-178
[20] Thomas L W, Lam C, Edwards S W. Mcl-1:the molecular regulation of protein function[J]. Febs Letters, 2010, 584(14):2981-2989
[21] Schwartz P S, Manion M K, Emerson C B, et al. 2-Methoxy antimycin reveals a unique mechanism for Bcl-x(L)inhibition[J].Molecular Cancer Therapeutics, 2007, 6(7):2073-2080
[22] Vela L, Marzo I. Bcl-2 family of proteins as drug targets for cancer chemotherapy:the long way of BH3 mimetics from bench to bedside[J]. Current Opinion in Pharmacology, 2015, 23:74-81
[23] Goodwin C M, Rossanese O W, Olejniczak E T, et al. Myeloid cell leukemia-1 is an important apoptotic survival factor in triple-negative breast cancer[J]. Cell Death&Differentiation, 2015, 22(12):2098-2106
[24] Quinn B A, Dash R, Azab B, et al. Targeting Mcl-1 for the therapy of cancer[J]. Expert Opinion on Investigational Drugs, 2011, 20(10):1397-1411
[25] Xu G, Liu T, Zhou Y, et al. 1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors:design, synthesis, and preliminary biological evaluation[J]. Bioorganic&Medicinal Chemistry, 2017, 25(20):5548-5556
[26] Qiao Z, Wang J, Wang H, et al. Inhibition of breast cancer cell proliferation by a newly developed photosensitizer chrolophyll derivative CPD4[J]. International Journal of Clinical&Experimental Medicine, 2014, 8(5):7381-7387
[27] Woo S M, Min K J, Bo R S, et al. YM155 enhances ABT-737-mediated apoptosis through Mcl-1 down regulation in Mcl-1-overexpressed cancer cells[J]. Molecular&Cellular Biochemistry,2017, 429(2):91-102
[28] Yu X, Wei L, Xia Z, et al. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis[J]. Bmc Cancer, 2017, 17(1):449
[29] Varadarajan S, Vogler M, Butterworth M, et al. Evaluation and critical assessment of putative MCL-1 inhibitors[J]. Cell Death&Differentiation, 2013, 20(11):1475-1484
[30] Zhao M Y, Chen H Y, Liu Y, et al. MiR-29 modulates multidrug resistance of gastric cancer cells by targeting Mcl-1[J]. World Chinese Journal of Digestology, 2016, 24(36):4781
[31] Pan R, Ruvolo V R, Wei J, et al. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor(-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia[J]. Blood, 2015, 126(3):363-372
[32] Kotschy A, Szlavik Z, Murray J, et al. The MCL-1 inhibitor S63845is tolerable and effective in diverse cancer models[J]. Nature, 2016,538(7626):477-482
[33] Letai A. S63845, an MCL-1 selective BH3 mimetic:another arrow in our quiver[J]. Cancer Cell, 2016, 30(6):834-835
[34] Merino D, Whittle J R, Vaillant F, et al. Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer[J]. Science Translational Medicine, 2017, 9(401)
[35] Bruncko M, Wang L, Sheppard GS, et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity[J].Journal of Medicinal Chemistry, 2015, 58(5):2180-2194
[36] Leverson J D, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263(navitoclax)[J]. Cell Death&Disease, 2015, 6(1):e1590
[37] DA Luedtke, Yubin Ge, Xiaojia Niu, et al. Inhibition of Mcl-1enhances cell death induced by the Bcl-2-selective inhibitor ABT-199in acute myeloid leukemia cells[J]. Signal Transduction and Targeted Therapy, 2017, 7(23):34785-34799
[38] Besbes S, Pocard M, Mirshahi M, et al. The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia[J]. Critical Reviews in Oncology/hematology, 2016, 100(1):32-36
[39] Liu T, Wan Y, Liu R, et al. Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors[J]. Bioorg Med Chem, 2017, 25(6):1939-1948
[40] Hird A W, Secrist J P, Adam A, et al. Abstract DDT01-02:AZD5991:A potent and selective macrocyclic inhibitor of Mcl-1 for treatment of hematologic cancer[J]. Cancer Research, 2017, 77(13Supplement):DDT01-02-DDT01-02