MDM2/MDMX双靶点抑制剂的研究进展
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摘要
p53是一种重要的肿瘤抑制蛋白,在大约50%的肿瘤细胞中p53因发生变异丧失肿瘤抑制功能,而在另外50%带有野生型p53的肿瘤细胞中其功能被抑制。MDM2和MDMX是p53的主要抑制剂,阻断MDM2和MDMX与p53的相互作用可以恢复野生型p53的功能,促使肿瘤细胞凋亡,因此有可能是一种新的治疗肿瘤的方法。本文中对不同类型的MDM2/MDMX双靶点抑制剂的研究进展进行了总结,并对MDM2/MDMX双靶点抑制剂的研发前景和方向进行了展望。
p53 is an important tumor suppressor which loses its function in about 50% of tumor cells because of mutation, while in another 50% of tumor cells with wild type p53, its function is inhibited. MDM2 and MDMX are major intrinsic inhibitors of p53. Blockage of the interactions between MDM2/MDMX and p53 can restore the function of wild type p53 and promote the apoptosis of tumor cells, and therefore is a potential novel therapy for the treatment of human tumors. In this review we summarize the progress of different classes of dual inhibitors of MDM2/MDMX, and provide perspection for the development of MDM2/MDMX dual inhibitors in future.
p53 is an important tumor suppressor which loses its function in about 50% of tumor cells because of mutation, while in another 50% of tumor cells with wild type p53, its function is inhibited. MDM2 and MDMX are major intrinsic inhibitors of p53. Blockage of the interactions between MDM2/MDMX and p53 can restore the function of wild type p53 and promote the apoptosis of tumor cells, and therefore is a potential novel therapy for the treatment of human tumors. In this review we summarize the progress of different classes of dual inhibitors of MDM2/MDMX, and provide perspection for the development of MDM2/MDMX dual inhibitors in future.
引文
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[20]Chen S,et al.Rapid identification of dual p53-MDM2/MDMX interaction inhibitors through virtual screening and hit-based substructure search[J].RSCAdvances,2017,7(16):9989-9997.
[21]Li Y,et al.Discovery of MD-224 as a first-in-Class,highly potent,and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression[J].J Am Chem Soc,2019,62(2):448-466.
[2]Zhao Y,et al.Small-molecule inhibitors of the MDM2-p53 Protein-Protein interaction(MDM2 Inhibitors)in clinical trials for cancer treatment:miniperspective[J].J Am Chem Soc,2015,58(3):1038-1052.
[3]Laurie N,et al.Inactivation of the p53 pathway in retinoblastoma[J].Nature,2006,444(7115):61-66.
[4]Kussie P H,et al.Structure of the MDM2 oncoprotein bound to the p53tumor suppressor transactivation domain[J].Science,1996,274(5289):948-953.
[5]Pazgier M,et al.Structural basis for high-affinity peptide inhibition of p53interaction with MDM2 and MDMX[J].Proc Natl Acad Sci USA,2009,106(12):4665-4670.
[6]Li C,et al,Apamin as a template for structure-based rational design of potent peptide activators of p53[J].Angew Chem Int Ed,2009,48(46):8712-8715.
[7]Kallen J,et al.Crystal structures of human MdmX(HdmX)in complex with p53 peptide analogues reveal surprising conformational changes[J].J Biol Chem,2009,284(13):8812-8821.
[8]Bernal F,et al.Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide[J].J Am Chem Soc,2007,129(9):2456-2457.
[9]Chang Y S,et al.Stapledα-helical peptide drug development:a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy[J].Proc Natl Acad Sci USA,2013,110(36):E3445-3454.
[10]US NIH.ClinicalTrials.gov.Safety of ALRN-6924 in patients with advanced solid tumors[EB/OL].(2014-10-07)[2015-01-20].https://www.Clinicaltrials.gov/ct2/show/NCT02264613.
[11]Qin L,et al.Efficient reactivation of p53 in cancer cells by a dual MDMX/MDM2 inhibitor[J].J Am Chem Soc,2014,136(52):18023-18033.
[12]Popowicz G M,et al.Structures of low molecular weight inhibitor bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2antagonist drug discovery[J].Cell Cycle,2010,9(5):1104-1111.
[13]Neochoritis C G,et al.2,3-Bis(1’H-indole)heterocycles:new p53/MDM2/MDMX antagonists[J].Bioorg Med Chem Lett,2015,25(24):5661-5666.
[14]Bista M,et al.On the mechanism of action of SJ-172550 in inhibitor of MDM4 and p53[J].PLoS One,2012,7(6):e37518.
[15]Lee J H,et al.Novel pyrrolopyrimidine-basedα-Helix mimetics:cell permeable inhibitors of protein-protein interactions[J].J Am Chem Soc,2011,133(4):676-679.
[16]Graves B,et al.Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization[J].Proc Natl Acad Sci USA,2012,109(29):11788-11793.
[17]Wu W,et al.Targeting RING domains of Mdm2-MdmX E3 complex activates apoptotic arm of the p53 pathway in leukemia/lymphoma cells[J].Cell Death Dis,2015,6(12):e2035-e2045.
[18]Vogel S M,et al.Lithocholic acid is an endogenous of MDM4 and MDM2[J].Proc Natl Acad Sci USA,2012,109(42):16906-16910.
[19]Golestanian S,et al.Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay[J].Life Sci,2016,145(Supplement C):240-246.
[20]Chen S,et al.Rapid identification of dual p53-MDM2/MDMX interaction inhibitors through virtual screening and hit-based substructure search[J].RSCAdvances,2017,7(16):9989-9997.
[21]Li Y,et al.Discovery of MD-224 as a first-in-Class,highly potent,and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression[J].J Am Chem Soc,2019,62(2):448-466.