Targeted Small Molecule Inhibitors for Inv(16) Leukemia

Inv(16) 白血病的靶向小分子抑制剂

• 批准号: 10520054
• 负责人: JOHN Hackett BUSHWELLER
• 金额: $ 66.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10520054
• 关键词: Acute Myelocytic Leukemia; Alleles; Apoptosis; Binding; Biochemistry; Biological Availability; CBFB gene; CBFbeta-MYH11 fusion protein; Cell model; Cells; Chemistry; Chimeric Proteins; Chromatin; Chromosomal translocation; Chromosome 16; Clinic; Collaborations; Complex; Core-Binding Factor; Cytotoxic Chemotherapy; Data; Diagnosis; Distal; Drug Kinetics; Engraftment; Enhancers; Ensure; FLT3 gene; Failure; Generations; Genes; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Health; Hematopoiesis; Human; In Vitro; Joints; Leukemic Cell; Literature; MYH11 gene; Malignant Neoplasms; Modeling; Mus; Mutation; Mutation Detection; Oral; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Point Mutation; Population; Property; Publications; RUNX1 gene; Rattus; Regimen; Relapse; Repression; Residual Neoplasm; Sampling; Solubility; Specificity; Structure; Tail; Testing; Time; Toxic effect; Translations; Treatment Side Effects; antileukemic activity; cancer initiation; cancer stem cell; chemotherapy; efficacy evaluation; improved; in vivo; inhibitor; inv(16)(p13q22); leukemia; leukemia initiating cell; leukemic stem cell; mouse model; novel; older patient; patient derived xenograft model; programs; promoter; protein protein interaction; relapse risk; self-renewal; small molecule; small molecule inhibitor; stem cell population; success; targeted treatment; therapeutically effective; transcription factor; treatment response; tumor

The gene encoding CBFβ (CBFB) is disrupted by the chromosome 16 inversion [inv(16)(p13q22)], associated with ~10% of acute myeloid leukemia (AML) in humans, resulting in a transcription factor fusion protein containing most of CBFβ fused to the coiled-coil tail region of smooth muscle myosin heavy chain (SMMHC). The CBFβ-SMMHC fusion protein acts as a dominant repressor of CBF function, binding RUNX1 and dysregulating the expression of multiple genes required for normal hematopoiesis. Current treatment utilizing cytotoxic chemotherapy results in 55% five year overall survival but only 17% for older patients. These data clearly indicate that targeted therapies that can improve the therapeutic response for inv(16) AML patients, particularly those who have relapsed or are at risk of relapse, is essential. Emerging literature suggests that inability to cure cancers with current therapies may be attributed to a population of cancer stem cells or cancer initiating cells that have long term self-renewal potential and can fully recapitulate tumor phenotype at time of relapse. Inv(16) AML is a good example of this failure because inv(16) patients invariably show, at time of relapse, the inv(16) rearrangement, while other mutations detected at diagnosis (RAS, FLT3ITD, or KIT) may or may not be detected. Our hypothesis is that small molecule inhibitors of the binding of CBFβ-SMMHC to RUNX1 could be effective therapeutic drugs that eradicate the leukemia initiating cell population in inv(16) leukemia, thereby achieving better long term survival. Recently we developed a first generation inhibitor which targets the protein-protein interaction between CBFβ-SMMHC and RUNX1. In this application, we are proposing two aims: Aim 1: Optimization of CBFβ-SMMHC inhibitors for improved potency and ADMET properties. We propose to modify our first generation inhibitor to improve ADMET properties to develop a potent orally bioavailable inhibitor for the treatment of inv(16) leukemia. Specifically, we propose to modify the structure of the linker by substitution of five-membered heterocycle based linkers in the bivalent inhibitors we have developed to improve the solubility and the oral bioavailability of the inhibitor. The most promising compounds will be profiled for pharmacokinetic properties in mice and rats, as well as using a panel of in vitro ADMET properties. The most promising compounds will be tested in Aim 2 for in vivo efficacy and efficacy against inv(16) patient samples. Aim 2: Characterization of promising CBFβ-SMMHC inhibitors using AML patient cells and mouse models for inv(16) AML. We propose to determine the efficacy and specificity of the most promising inhibitors in reducing the survival of inv(16) AML compared to non-inv(16) AML patient samples in vitro. We also propose to determine their efficacy in mice, utilizing in vivo treatment in a genetically engineered model (GEM) and a patient-derived xenograft (PDX) mouse model for inv(16) acute myeloid leukemia. The inhibitors will be tested for their antileukemic activity in reducing engraftment, leukemia latency, and leukemia burden, as well as in eliminating the leukemia stem cells in recipient mice.

编码CBFβ（CBFB）的基因被16号染色体倒位[inv（16）（p13 q22）]破坏， 与约10%的人类急性髓性白血病（AML）相关，导致转录因子融合 一种含有大部分CBFβ的蛋白质，与平滑肌肌球蛋白重链的卷曲螺旋尾区融合 （SMMHC）。CBFβ-SMMHC融合蛋白作为CBF功能的显性阻遏物，结合RUNX 1和 正常造血所需的多种基因表达失调。目前的治疗利用 细胞毒性化疗导致55%的五年总生存率，但对于老年患者仅为17%。这些数据 清楚地表明，靶向治疗可以改善inv（16）AML患者的治疗反应， 特别是那些已复吸或有可能复吸的人士。新出现的文献表明， 目前的疗法无法治愈癌症可能归因于癌症干细胞或癌症的群体 具有长期自我更新潜力并可在肿瘤发生时完全重现肿瘤表型的起始细胞。 复发Inv（16）AML是这种失败的一个很好的例子，因为inv（16）患者总是显示，在治疗时， 复发，inv（16）重排，而在诊断时检测到的其他突变（RAS，FLT 3 ITD或KIT）可能或 可能不会被检测到。我们的假设是CBFβ-SMMHC与RUNX 1结合的小分子抑制剂， 可能是根除inv（16）白血病中的白血病起始细胞群的有效治疗药物， 从而获得更好的长期存活。最近，我们开发了第一代抑制剂， CBFβ-SMMHC和RUNX 1之间的蛋白质-蛋白质相互作用。在本申请中，我们提出两个目的： 目的1：优化CBFβ-SMMHC抑制剂以改善效力和ADMET性质。我们 我建议修改我们的第一代抑制剂，以改善ADMET的性能，以开发一种有效的口服 用于治疗inv（16）白血病的生物可利用的抑制剂。具体而言，我们建议修改 我们已经开发了二价抑制剂， 提高抑制剂的溶解度和口服生物利用度。最有前途的化合物将被概述 用于小鼠和大鼠的药代动力学特性，以及使用一组体外ADMET特性。最 在目标2中将测试有希望的化合物的体内功效和对inv（16）患者样品的功效。 目的2：使用AML患者细胞和小鼠模型表征有前景的CBFβ-SMMHC抑制剂 inv（16）AML。我们建议确定最有前途的抑制剂在降低 与非inv（16）AML患者样品相比，inv（16）AML患者样品的体外存活率。我们还建议确定 在基因工程模型（GEM）和患者来源的 inv（16）急性髓性白血病异种移植（PDX）小鼠模型。将测试抑制剂的 在减少植入、白血病潜伏期和白血病负荷以及消除 白血病干细胞移植到受体小鼠体内。

项目成果

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking.

RUNX1-CBFβ 转录因子复合物的抑制会损害乳腺上皮细胞身份：有丝分裂基因书签可能稳定的表型。

• DOI: 10.18632/oncotarget.27637
• 发表时间: 2020
• 期刊: Oncotarget
• 作者: Rose,JoshuaT;Moskovitz,Eliana;Boyd,JosephR;Gordon,JonathanA;Bouffard,NicoleA;Fritz,AndrewJ;Illendula,Anuradha;Bushweller,JohnH;Lian,JaneB;Stein,JanetL;Zaidi,SayyedK;Stein,GaryS
• 通讯作者: Stein,GaryS

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.

基因调控网络分析预测 FLT3-ITD AML 生长所需的协作转录因子调节子。

• DOI: 10.1101/2023.07.18.549495
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Coleman,DanielJL;Keane,Peter;Luque-Martin,Rosario;Chin,PaulynnS;Blair,Helen;Ames,Luke;Kellaway,SophieG;Griffin,James;Holmes,Elizabeth;Potluri,Sandeep;Assi,SalamA;Bushweller,John;Heidenreich,Olaf;Cockerill,PeterN;Bonifer,
• 通讯作者: Bonifer,

Synthesis, Crystallography, and Anti-Leukemic Activity of the Amino Adducts of Dehydroleucodine.

脱氢酸氨酸的氨基加合物的合成，晶体学和抗白血病活性。

• DOI: 10.3390/molecules25204825
• 发表时间: 2020-10-20
• 期刊: Molecules (Basel, Switzerland)
• 作者: Ordóñez PE;Mery DE;Sharma KK;Nemu S;Reynolds WF;Enriquez RG;Burns DC;Malagón O;Jones DE;Guzman ML;Compadre CM
• 通讯作者: Compadre CM

Targeting transcription factors in cancer - from undruggable to reality.

• DOI: 10.1038/s41568-019-0196-7
• 发表时间: 2019-11
• 期刊: Nature reviews. Cancer
• 作者: Bushweller JH

Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.

• DOI: 10.1038/s41698-021-00183-2
• 发表时间: 2021-05-26
• 期刊: NPJ precision oncology
• 影响因子: 7.9
• 作者: Sugita M;Wilkes DC;Bareja R;Eng KW;Nataraj S;Jimenez-Flores RA;Yan L;De Leon JP;Croyle JA;Kaner J;Merugu S;Sharma S;MacDonald TY;Noorzad Z;Panchal P;Pancirer D;Cheng S;Xiang JZ;Olson L;Van Besien K;Rickman DS;Mathew S;Tam W;Rubin MA;Beltran H;Sboner A;Hassane DC;Chiosis G;Elemento O;Roboz GJ;Mosquera JM;Guzman ML
• 通讯作者: Guzman ML