摘要
Mixed lineage leukemia 1(MLL1)是组蛋白甲基转移酶SET家族的成员之一。MLL1与WDR5、RbBP5、Ash2L和DPY-30组成MLL1甲基转移酶复合物调控组蛋白H3的第4位赖氨酸的甲基化水平,对造血系统的发育和血细胞的更新至关重要。部分白血病患者体内存在因MLL1基因易位而产生的致癌蛋白——MLL1融合蛋白,MLL1融合蛋白在发挥其致癌作用时需要功能完整的MLL1酶复合物,故靶向MLL1-WDR5的蛋白-蛋白相互作用成为治疗MLL1融合型白血病的潜在策略。本文对MLL1-WDR5蛋白-蛋白相互作用的生物学机制、结构信息以及抑制剂进行了系统的总结,并结合已报道数据对该领域进行了展望,以期为后续研究提供参考。
表观遗传学是近年来生命科学界最热门的领域之一,其涉及的生物学活动覆盖了从胚胎发育到动物毛发颜色调节等各个环节。表观遗传还参与众多疾病的起始、发展和维持,如:糖尿
SET1家族是负责调节组蛋白H3的第4位赖氨酸(H3K4)甲基化过程的蛋白家族,因其特有的SET结构域而得名。SET1家族可以通过将甲基载体S-5'-腺苷-L-蛋氨酸(SAM)上的甲基转移至H3K4而实现组蛋白的甲基化。SET1家族成员有MLL1-4(mixed lineage leukemia 1-4)、SET1a和SET1b,其中MLL1是研究最为深入的一个成员。研究发现,组蛋白甲基转移酶MLL1与多种肿瘤的发生、发展相关,成为近年来治疗肿瘤的热门靶
MLL1又称组蛋白赖氨酸甲基转移酶2(KMT2A),因其可诱发混合谱系白血病(mixed lineage leukemia)得

图1 MLL1蛋白翻译后修饰和MLL1甲基转移酶复合物
A: 野生型全长MLL1蛋白; B: MLL1被taspase1酶切后重新形成的成熟的野生型MLL1蛋白,然后和WDR5、RbBP5 (retinoblastoma binding protein 5)、Ash2L (absent small or homeotic-2-Like) 和DPY30 (Dumpy-30) 形成MLL1甲基转移酶复合物MBD: 甲基结合结构域; AT: AT-钩; SNL: 斑点核定位; CXXC: Cys-Xaa-Xaa-Cys; RD2: 抑制结构域2; PHD: 植物同源结构域; BD: 溴结构域;FYRC: F/Y-rich C; FYRN: F/Y-rich N; TAD: 转录激活结构域; WIN: WDR5相互作用; SET: SET结构域
MLL1的主要生物学功能是在胚胎发育、造血和神经发育过程中通过调节组蛋白H3K4的甲基化状态,维持下游Hox(homeobox)基因表达,而Hox基因在造血功能、干细胞自我更新等生理过程中起着重要作
混合谱系白血病基因(MLL gene)是三胸腺果蝇基因(drosophila trithorax)的同源基

图2 染色体重组导致MLL1融合蛋白的形成
A:全长的野生型MLL1蛋白;B:MLL融合蛋白
WT-MLL1是MLL1-FPs相关白血病发生、发展和维持所不可或缺的。MLL基因重排仅发生在一个等位基因上,MLL1-FPs的靶基因是WT-MLL1靶基因的子集。若野生型MLL基因被敲除,仅MLL1-FPs无法诱导和维持白血
破坏MLL1甲基转移酶复合物正常的生理功能,降低H3K4的甲基化水平,减少MLL1-FPs的结合位点,从而降低MLL1-FPs被招募到靶基因的概率是治疗融合蛋白诱导的白血病的策略之一。WDR5是MLL1甲基转移酶复合物的核心组件,是MLL1复合物发挥正常生理功能的基石之一。WDR5通过和MLL1的Win序列相互作用,招募MLL1复合物的其他成员(RbBP5、Ash2L和DPY-30)组成功能完整的MLL1甲基转移酶复合物(
WDR5是典型的WD40重复域蛋白家族的成员。总体呈游泳圈状,有7个反式β螺旋桨域,每个叶片由4个反式平行的β折叠组成,其中每个叶片以保守的丝氨酸-组氨酸(SH)开始,以色氨酸-天冬氨酸(WD)结束,大小为34 kD。7个结构域环绕在一起组成一个贯穿蛋白质顶部和底部的中心腔(

图3 WDR5的结构和MLL1-WDR5 PPI抑制剂的主要作用位点
MLL1-WDR5相互作用界面位于WDR5蛋白的顶部,被7个七叶β-螺旋桨域包
靶向MLL1-WDR5 PPI抑制剂最早报道于2010年,距今已有十多年的研发历史。根据小分子的结构和类型分类主要有拟肽类、多取代苯基哌嗪类、芳香五元杂环类(后两者的分类主要依据氢键网络区的结合基团结构而定)以及基于这些化合物衍生的工具分子(

图4 不同类型的代表MLL1-WDR5蛋白-蛋白相互作用(PPI)抑制剂
肽类和拟肽类小分子抑制剂主要由美国密歇根大学的王少萌课题组开发。其通过使用多肽的基序简化,将MLL1中的WIN motif简化为三肽Ac-ARA-NH2(Ki = 120 nmol/L

图5 拟肽类MLL1-WDR5 PPI抑制剂
王少萌课题组继续对拟肽MM-101进行改造得到了环状拟肽MM-401(IC50 = 0.9 nmol/L,

图6 WDR5与多肽和拟态的结合模式对比
A:WIN motif和WDR5的结合模式(PBD:2H14);B:MM-589和WDR5的结合模式(PBD:5VFC)
多取代苯基哌嗪类化合物来自于筛选得到的小分子化合物WDR5-0102,该化合物由Guillermo课题

图7 苯甲酰胺类MLL1-WDR5 PPI抑制剂
WDR5-0102结构中包含了和精氨酸结合口袋结合的N-甲基哌嗪,哌嗪和中心苯环相连,邻位则是苯甲酰氨基。因此WDR5-0102是第一个苯甲酰胺类化合物。WDR5-0102靶标结合活性适中、结构简单,是优良的苗头化合物(Kd = 3.0 ± 1 μmol/L

图8 WDR5-47和WDR5的结合模式(PBD:4IA9)
基于WDR5-47,中国药科大学的尤启冬课题组在WDR5-47的中心苯环的5位使用吡啶替换硝基得到了化合物23,其靶标活性进一步提升(IC50 = 104 nmol/L
除DDO-2117外,尤启冬课题组还使用其他策略对WDR5-47进行优化,获得了2个不同结构的苯甲酰类化合物(
同样基于化合物WDR5-47,尤启冬课题组使用骨架跃迁策略得到了嘧啶氨基苯类化合物,通过将WDR5-47的苯甲酰胺基团替换为4-氯-5-氨基取代嘧啶,中心苯环硝基取代为4-(N,N-二甲氨酰)苯基,并在中心苯环5号位引入F原子得到了DDO-2213(

图9 嘧啶氨基苯类MLL1-WDR5 PPI抑制剂
在WDR5-47的结构基础上,Al-Awar课题组根据片段筛选,将取代苯甲酰胺替换为4-(三氟甲基)吡啶酮,并将WDR5-47的硝基替换为3-甲基吗啉取代的苯环得到OICR-9429(

图10 三氟甲基吡啶酮类MLL1-WDR5 PPI抑制剂
在OICR-9429的基础上,Al-Awar课题组继续优化了靶标活性和成药性。在中心苯环C-4处的引入F原子,并使用4-(嘧啶-2-基)吗啉取代中心苯环C-5处的4-苄基吗啉,同时在N-甲基哌嗪的2号位引入甲基后得到化合物7。化合物7是第一个皮摩尔级别的MLL1-WDR5 PPI抑制剂(Kd = 0.06 nmol/L),有小于百纳摩尔的体外抗增殖活性(MV4-11
2018年,Fesik课题
Fesik课题组基于NMR的片段筛选得到了抑制剂的基本片段——2-苯基-6,7-二氢-5H-吡咯并[1,2-a]咪唑。环状咪唑基团占据P1并与Phe133和Phe263形成π-π堆叠,咪唑3号氮原子通过氢键和Cys261的羰基相互作用。进而在苯环3号位引入苄基取代的苯甲酰胺将化合物的结合区扩展P5,并通过构象限制进一步优化获得化合物6e(

图11 芳香五元杂环类MLL1-WDR5 PPI抑制剂
2019年,Fesik课题组基于碎片筛选得到了另一种结构的MLL1-WDR5 PPI抑制剂。他们得到了初始精氨酸模拟片段——咪唑胺结构,使用苄基酰胺将分子延伸至P5,通过修饰苄基以增强和P5的相互作用,并在中心苯环上引入F指向P2得到化合物C3。同时筛选到的另一个片段—— 5-(1H-咪唑-3-甲基)糠醛酸,他们将酸和苄胺缩合以利用苄基占据P5口袋,并用2-氟-6-甲基吡啶代替F来占据P2,在原有咪唑的C-2位引入亚氨基增强和氢键网络区的相互作用得到化合物C6,因此靶标活性也更

图12 WDR5和芳香五元杂环类抑制剂的相互作用
A:化合物6b(6e同系列化合物)和WDR5的结合模式(PBD:6DAS);B:化合物16和WDR5的结合模式(PBD:6UCS)
2017年,Vázquez课题组报道了基于多肽类光调控WIN site抑制剂。抑制剂基于WIN motif,引入4-(4′-氨甲基苯基偶氮)苯甲酸(AMPB)作为光调控元件,获得靶标活性较好的光调控制剂(Ki = 1.24 nmol/L)。用光处理后,抑制剂的顺反异构发生改变,导致靶标活性变化,体外MLL1的甲基转移酶活性也随之改变。化合物以微摩尔GI50抑制小鼠骨髓细胞的增殖,顺式和反式异构体之间有明显的活性差

图13 基于MLL1-WDR5 PPI抑制剂的工具分子
本文对靶向MLL1-WDR5蛋白-蛋白相互作用的小分子抑制剂的药理学机制以及WDR5蛋白Win-site结合位点结构信息进行了总结,介绍了已公开的各个结构类型的MLL1-WDR5蛋白-蛋白相互作用小分子抑制剂。经过十几年的发展,人们对MLL1的生理功能日趋了解,靶向MLL1的新途径也不断被发现。MLL1-WDR5蛋白-蛋白相互作用作为肿瘤治疗的新策略越来越受到研究者的关注,目前针对MLL1-WDR5 PPI抑制剂的开发依然处于前期研究阶段,尚未有小分子抑制剂进入临床研究,但已有多个候选化合物涌现。
MLL1-WDR5 PPI抑制剂的研究虽已取得较好的进展,亦具有较大的开发潜力,但依然存在一些不足。首先,目前报道的分子虽然数量较多,但结构类型较为单一,并且无论是多肽类抑制剂还是非肽类的小分子抑制剂都含有较强的碱性基团(哌嗪、胍基和含氮芳香五元杂环等),这些结构特征可能导致分子成药性不佳(如多肽类分子体内代谢稳定性和透膜性较差、部分多取代苯基哌嗪类小分子的极性较强)。其次,部分MLL1-WDR5 PPI抑制剂虽然具有较好的体外活性,但目前体内研究的数据较少,现有抑制剂的有效性还需要更多的实验支撑。因此,针对MLL1-WDR5 PPI抑制剂的研究,不仅要在原有分子的基础上继续优化其成药性,还需寻找更多结构新颖的小分子抑制剂,同时抑制剂的体内有效性也有待进一步阐明。此外,利用新策略研发出更多的工具分子,可以为进一步探究MLL1相关的生物学机制提供分子基础。
除了靶向MLL1-WDR5蛋白-蛋白相互作用,在WDR5蛋白上发现了另外一个蛋白结合空
References
Ling C,Rönn T. Epigenetics in human obesity and type 2 diabetes[J]. Cell Metab,2019,29(5):1028-1044. [百度学术]
Cromby J,Chung E,Papadopoulos D,et al. Reviewing the epigenetics of schizophrenia[J]. J Ment Heal,2019,28(1):71-79. [百度学术]
Duruisseaux M,Esteller M. Lung cancer epigenetics:from knowledge to applications[J]. Semin Cancer Biol,2018,51:116-128. [百度学术]
Eckschlager T,Plch J,Stiborova M,et al. Histone deacetylase inhibitors as anticancer drugs[J]. Int J Mol Sci,2017,18(7):1414. [百度学术]
Jones PA,Issa JPJ,Baylin S. Targeting the cancer epigenome for therapy[J]. Nat Rev Genet,2016,17(10):630-641. [百度学术]
Jones PA,Baylin SB. The epigenomics of cancer[J]. Cell,2007,128(4):683-692. [百度学术]
Berger SL,Kouzarides T,Shiekhattar R,et al. An operational definition of epigenetics[J]. Genes Dev,2009,23(7):781-783. [百度学术]
Sheikhpour M,Maleki M,Ebrahimi Vargoorani M,et al. A review of epigenetic changes in asthma:methylation and acetylation[J]. Clin Epigenetics,2021,13(1):65. [百度学术]
Hyun K,Jeon J,Park K,et al. Writing,erasing and reading histone lysine methylations[J]. Exp Mol Med,2017,49(4):e324. [百度学术]
Kaniskan HU,Martini ML,Jin J. Inhibitors of protein methyltransferases and demethylases[J]. Chem Rev,2018,118(3):989-1068. [百度学术]
Ruthenburg AJ,Allis CD,Wysocka J. Methylation of lysine 4 on histone H3:intricacy of writing and reading a single epigenetic mark[J]. Mol Cell,2007,25(1):15-30. [百度学术]
Guenther MG,Jenner RG,Chevalier B,et al. Global and hox-specific roles for the MLL1 methyltransferase[J]. Proc Natl Acad Sci U S A,2005,102(24):8603-8608. [百度学术]
Dou Y,Milne TA,Tackett AJ,et al. Physical association and coordinate function of the H3K4 methyltransferase MLL1 and the H4K16 acetyltransferase MOF[J]. Cell,2005,121(6):873-885. [百度学术]
Daigle SR,Olhava EJ,Therkelsen CA,et al. Potent inhibition of dot1l as treatment of MLL-fusion leukemia[J]. Blood,2013,122(6):1017-1025. [百度学术]
Grembecka J,He S,Shi A,et al. Menin-MLL1 inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia[J]. Nat Chem Biol,2012,8(3):277-284. [百度学术]
Hess JL. MLL:a histone methyltransferase disrupted in leukemia[J]. Trends Mol Med,2004,10(10):500-507. [百度学术]
Glaser S,Schaft J,Lubitz S,et al. Multiple epigenetic maintenance factors implicated by the loss of MLL2 in mouse development[J]. Development,2006,133(8):1423-1432. [百度学术]
Butler LH,Slany R,Cui X,et al. The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures[J]. Blood,1997,89(9):3361-3370. [百度学术]
Tkachuk DC,Kohler S,Cleary ML. Involvement of a homolog of drosophila trithorax by 11q23 chromosomal translocations in acute leukemias[J]. Cell,1992,71(4):691-700. [百度学术]
Cosgrove MS,Patel A. Mixed lineage leukemia:a structure-function perspective of the MLL1 protein[J]. FEBS J,2010,277(8):1832-1842. [百度学术]
Gu Y,Nakamura T,Alder H,et al. The T(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene,related to drosophila trithorax,to the AF-4 gene[J]. Cell,1992,71(4):701-708. [百度学术]
Yokoyama A,Kitabayashi I,Ayton PM,et al. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties[J]. Blood,2002,100(10):3710-3718. [百度学术]
Argiropoulos B,Humphries RK. Hox genes in hematopoiesis and leukemogenesis[J]. Oncogene,2007,26(47):6766-6676. [百度学术]
Dou Y,Hess JL. Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia[J]. Int J Hematol,2008,87(1):10-18. [百度学术]
Milne TA,Kim J,Wang GG,et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the hoxa9 locus in leukemogenesis[J]. Mol Cell,2010,38(6):853-863. [百度学术]
Chang PY,Hom RA,Musselman CA,et al. Binding of the MLL1 PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription[J]. J Mol Biol,2010,400(2):137-144. [百度学术]
Mcmahon KA,Hiew SY,Hadjur S,et al. MLL has a critical role in fetal and adult hematopoietic stem cell self-renewal[J]. Cell Stem Cell,2007,1(3):338-345. [百度学术]
Ansari KI,Kasiri S,Mandal SS. Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo[J]. Oncogene,2013,32(28):3359-3370. [百度学术]
Scharf S,Zech J,Bursen A,et al. Transcription linked to recombination:a gene-internal promoter coincides with the recombination hot spot Ⅱ of the human MLL gene[J]. Oncogene,2007,26(10):1361-1371. [百度学术]
Yu BD,Hanson RD,Hess JL,et al. MLL,a mammalian trithorax-group gene,functions as a transcriptional maintenance factor in morphogenesis[J]. Proc Natl Acad Sci U S A,1998,95(18):10632-10636. [百度学术]
Winters AC,Bernt KM. MLL-rearranged leukemias-an update on science and clinical approaches[J]. Front Pediatr,2017,5:4. [百度学术]
Ayton PM,Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins[J]. Oncogene,2001,20(40):5695-5707. [百度学术]
Meyer C,Kowarz E,Hofmann J,et al. New insights to the MLL recombinome of acute leukemias[J]. Leukemia,2009,23(8):1490-1499. [百度学术]
Luo Z,Lin C,Shilatifard A. The super elongation complex(SEC) family in transcriptional control[J]. Nat Rev Mol Cell Biol,2012,13(9):543-547. [百度学术]
Nguyen AT,Zhang Y. The diverse functions of Dot1 and H3K79 methylation[J]. Genes Dev,2011,25(13):1345-1358. [百度学术]
Muntean AG,Hess JL. The pathogenesis of mixed-lineage leukemia[J]. Annu Rev Pathol,2012,7:283-301. [百度学术]
Milne TA,Martin ME,Brock HW,et al. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus,promoting transcription and multiple histone modifications[J]. Cancer Res,2005,65(24):11367-11374. [百度学术]
Thiel AT,Blessington P,Zou T,et al. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele[J]. Cancer Cell,2010,17(2):148-159. [百度学术]
Wang QF,Wu G,Mi S,et al. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome[J]. Blood,2011,117(25):6895-6905. [百度学术]
Dou Y,Milne TA,Ruthenburg AJ,et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components[J]. Nat Struct Mol Biol,2006,13(8):713-719. [百度学术]
Patel A,Dharmarajan V,Vought VE,et al. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1(MLL1) core complex[J]. J Biol Chem,2009,284(36):24242-24256. [百度学术]
Karatas H,Townsend EC,Cao F,et al. High-affinity,small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction[J]. J Am Chem Soc,2013,135(2):669-682. [百度学术]
Grebien F,Vedadi M,Getlik M,et al. Pharmacological targeting of the WDR5-MLL interaction in C/EBPα n-terminal leukemia[J]. Nat Chem Biol,2015,11(8):571-578. [百度学术]
Odho Z,Southall SM,Wilson JR. Characterization of a novel WDR5-binding site that recruits RbBP5 through a conserved motif to enhance methylation of histone H3 lysine 4 by mixed lineage leukemia protein-1[J]. J Biol Chem,2010,285(43):32967-32976. [百度学术]
Gregory GD,Vakoc CR,Rozovskaia T,et al. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes[J]. Mol Cell Biol,2007,27(24):8466-8479. [百度学术]
Chen Z,Yan CT,Dou Y,et al. The role of a newly identified SET domain-containing protein,SETD3,in oncogenesis[J]. Haematologica,2013,98(5):739-743. [百度学术]
Wang F,Jeon KO,Salovich JM,et al. Discovery of potent 2-aryl-6,7-dihydro-5 h-pyrrolo[1,2-a]imidazoles as WDR5-win-site inhibitors using fragment-based methods and structure-based design[J]. J Med Chem,2018,61(13):5623-5642. [百度学术]
Getlik M,Smil D,Zepeda-Velzquez C,et al. Structure-based optimization of a small molecule antagonist of the interaction between WD repeat-containing protein 5(WDR5) and mixed-lineage leukemia 1(MLL1)[J]. J Med Chem,2016,59(6):2478-2496. [百度学术]
Zhang P,Lee H,Brunzelle JS,et al. The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases[J]. Nucleic Acids Res,2012,40(9):4237-4246. [百度学术]
Patel A,Vought VE,Dharmarajan V,et al. A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex[J]. J Biol Chem,2008,283(47):32162-32175. [百度学术]
Karatas H,Townsend EC,Bernard D,et al. Analysis of the binding of mixed lineage leukemia 1(MLL1) and histone 3 peptides to WD repeat domain 5(WDR5) for the design of inhibitors of the MLL1-WDR5 interaction[J]. J Med Chem,2010,53(14):5179-5185. [百度学术]
Cao F,Townsend EC,Karatas H,et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia[J]. Mol Cell,2014,53(2):247-261. [百度学术]
Karatas H,Li Y,Liu L,et al. Discovery of a highly potent,cell-permeable macrocyclic peptidomimetic(MM-589) targeting the WD repeat domain 5 protein(WDR5)-mixed lineage leukemia(MLL) protein-protein interaction[J]. J. Med. Chem.,2017,60(12):4818-4839. [百度学术]
Senisterra G,Wu H,Allali-Hassani A,et al. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5[J]. Biochem J,2013,449(1):151-159. [百度学术]
Bolshan Y,Getlik M,Kuznetsova E,et al. Synthesis,optimization,and evaluation of novel small molecules as antagonists of WDR5-MLL interaction[J]. ACS Med Chem Lett,2013,4(3):353-357. [百度学术]
Li DD,Chen WL,Xu XL,et al. Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5[J]. Eur J Med Chem,2016,118:1-8. [百度学术]
Chen WL,Chen X,Li DD,et al. Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity[J]. Eur J Med Chem,2021,223:113677. [百度学术]
Chen WL,Chen X,Li DD,et al. Discovery of DDO-2213 as a potent and orally bioavailable inhibitor of the WDR5-mixed lineage leukemia 1 protein-protein interaction for the treatment of MLL fusion leukemia[J]. J Med Chem,2021,64(12):8221-8245. [百度学术]
Rima AA,Methvin I,Babu J,et al. Inhibitor of WDR5 protein-protein binding:WO2017147700A1[P]. 2017-09-08. [百度学术]
Rima AA,Methvin I,Babu J,et al. Inhibitor of WDR5 protein-protein binding:WO2019046944A1[P]. 2019-03-04. [百度学术]
Aho ER,Wang J,Gogliotti RD,et al. Displacement of WDR5 from chromatin by a WIN site inhibitor with picomolar affinity[J]. Cell Rep,2019,26(11):2916-2928.e13. [百度学术]
Tian JH,Teuscher KB,Aho ER,et al. Discovery and structure-based optimization of potent and selective WD repeat domain 5(WDR5) inhibitors containing a dihydroisoquinolinone bicyclic core[J]. J Med Chem,2020,63(2):656-675. [百度学术]
Albert L,Xu J,Wan RW,et al. Controlled inhibition of methyltransferases using photoswitchable peptidomimetics:towards an epigenetic regulation of leukemia[J]. Chem Sci,2017,8(6):4612-4618. [百度学术]
Chen WL,Li DD,Wang ZH,et al. Design,synthesis,and initial evaluation of affinity-based small molecular probe for detection of WDR5[J]. Bioorg Chem,2018,76:380-385. [百度学术]
Jian J,Dongxu L,Jing L,et al. Wd40 repeat domain protein 5(WDR5) degradation/destruction compound and method of use:WO2019246570A1[P]. 2019-12-26. [百度学术]
Avdic V,Zhang P,Lanouette S,et al. Structural and biochemical insights into MLL1 core complex assembly[J]. Structure,2011,19(1):101-108. [百度学术]