单次静脉注射AZD5991可产生从肿瘤生长抑制(TGI)到肿瘤消退(TR)的剂量依赖性抗肿瘤作用。用药10 d后,AZD5991在10和30 mg/kg剂量下TGI分别为52%和93% (p<0.0001)。在同一时间点,AZD5991在60 mg/kg剂量组7只小鼠中有6只小鼠的TR达到99%,未检测到肿瘤,而在100 mg/kg剂量组7只小鼠中有7只小鼠出现完全TR。...
在过去的5−10年中,在(专利)文献中披露了各种有效的、选择性的Mcl-1抑制剂,一些化合物达到临床开发,尽管结果混合和某些毒性担忧。认识到抑制Mcl-1功能需要阻断蛋白−蛋白相互作用的事实,大多数开发的抑制剂都是相当大的分子,许多特性如Log P、PSA和...
有趣的是,抑制c-Myc增强了AZD5991诱导的细胞色素c释放和随后的凋亡诱导。AZD5991在体外增强FLT3抑制剂Gilteritinib和MRX-2843对FLT3突变AML的抗白血病活性,值得进一步研究。 10058-F4(Abmole,M2352,纯度>98%)是一种c-Myc抑制剂,特异性抑制c-Myc-Max相互作用,且抑制c-Myc靶基因表达的转录激活。Cytarabine (AraC)...
Here, we describe the discovery, mechanism of action, and preclinical efficacy of an Mcl-1 inhibitor, AZD5991, in MM and AML models that support clinical evaluation of AZD5991 in patients with hematological malignancies [https://ClinicalTrials.gov/show/NCT03218683]. Results Discovery of macrocyclic...
促生存蛋白骨髓细胞白血病 1 (Mcl-1) 是 Bcl-2 家族的抗凋亡成员,与肿瘤侵袭性、生存不良和耐药性相关。Mcl-1 抑制剂的开发意味着阻断蛋白质-蛋白质相互作用,通常需要对大而复杂的分子进行漫长的优化过程。在此,描述了使用 DNA 编码的化学文库合成和筛选来直接生成复杂但构象优先的大环化合物,作为 Mcl-1抑制...
Herein we discuss some key learnings, distilled from our experience developing potent and selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been selected from recent oncology research projects, demonstrating how 1D NMR conformational signatures can ...
Toward this goal, extensive pre-formulation characterization of AZD5991 including solid form analysis, pH-solubility profiling and solubility determination in cosolvents and other solubilizing media were carried out.Results & discussion Crystalline Form A, which is more stable in aqueous solution and ...
In VitroAZD5991是有效的Mcl-1抑制剂,具有高选择性。AZD5991可与Mcl-1直接结合,通过激活依赖于Bak的线粒体凋亡途径快速诱导癌细胞凋亡,对骨髓瘤和急性髓系白血病效果尤为显著(GI50 < 100nM)。在一系列血液肿瘤和实体瘤来源的细胞系中,AZD5991有倾向性地杀死血液细胞[1][3]。
20.作为一种可能的实施方式,所述的药盒中,所述mcl-1抑制剂包括特异性抑制mcl-1的小分子化合物;特异性干扰mcl-1基因表达的干扰分子;特异性敲除mcl-1基因的基因编辑试剂;或特异性与mcl-1基因编码的蛋白结合的抗体或配体;或特异性诱导mcl-1降解的蛋白降解诱导剂。
AZD5991Acute myeloid leukemiaMcl-1c-MycApoptosis - Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients...doi...