Targeted Small Molecule Inhibitors for Inv(16) Leukemia

Inv(16) 白血病的靶向小分子抑制剂

基本信息

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
项目类别：
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

项目摘要

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) 的基因因 16 号染色体倒位而被破坏 [inv(16)(p13q22)]，与约 10% 的人类急性髓系白血病 (AML) 相关，导致转录因子融合含有大部分 CBFβ 的蛋白质融合到平滑肌肌球蛋白重链的卷曲螺旋尾部区域 (SMMHC)。CBFβ-SMMHC 融合蛋白作为 CBF 功能的显性阻遏蛋白，结合 RUNX1 和目前的治疗方法导致正常造血所需的多个基因表达失调。细胞毒性化疗的五年总生存率为 55%，但老年患者的五年总生存率仅为 17%。明确表明靶向治疗可以改善 inv(16) AML 患者的治疗反应，新出现的文献表明，特别是那些已经复发或有复发风险的人，这一点至关重要。目前的疗法无法治愈癌症可能是由于癌症干细胞群体或癌症具有长期自我更新潜力并且可以在肿瘤发生时完全重现肿瘤表型的起始细胞 Inv(16) AML 是这种失败的一个很好的例子，因为 inv(16) 患者总是在复发时表现出来。复发、inv(16) 重排，而诊断时检测到的其他突变（RAS、FLT3ITD 或 KIT）可能或我们的假设是 CBFβ-SMMHC 与 RUNX1 结合的小分子抑制剂可能未被检测到。可能是消除 inv(16) 白血病中白血病起始细胞群的有效治疗药物，从而实现更好的长期生存。最近，我们开发了第一代抑制剂。 CBFβ-SMMHC 和 RUNX1 之间的蛋白质-蛋白质相互作用在此应用中，我们提出了两个目标：目标 1：优化 CBFβ-SMMHC 抑制剂以提高效力和 ADMET 特性。建议修改我们的第一代抑制剂以改善 ADMET 特性，从而开发一种有效的口服药物具体来说，我们建议修改其结构，用于治疗 inv(16) 白血病。通过在我们开发的二价抑制剂中取代基于五元杂环的连接体来连接提高抑制剂的溶解度和口服生物利用度将描述最有前途的化合物。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。有前途的化合物将在目标 2 中测试其体内功效和针对 inv(16) 患者样本的功效。目标 2：使用 AML 患者细胞和小鼠模型表征有前景的 CBFβ-SMMHC 抑制剂对于 inv(16) AML，我们建议确定最有希望的抑制剂在减少疾病方面的功效和特异性。我们还建议在体外确定 inv(16) AML 与非 inv(16) AML 患者样本的存活率。利用基因工程模型 (GEM) 和患者来源的体内治疗，在小鼠中发挥功效将测试 inv(16) 急性髓性白血病的异种移植 (PDX) 小鼠模型的抑制剂。抗白血病活性，可减少植入、白血病潜伏期和白血病负担，以及消除受体小鼠的白血病干细胞。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-ALL.

患者来源的骨髓球体揭示了儿科 B-ALL 中由间充质缺氧生态位支持的白血病起始细胞。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Balandrán, Juan Carlos;Dávila;Sandoval;Zamora;Terán;García;Limón;Armenta;Rodríguez;Leon
通讯作者：
Leon

BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.

BCL6 维持原代人急性髓系白血病细胞的存活和自我更新。

DOI：
10.1182/blood.2019001745
发表时间：
2020-09-10
期刊：
Blood
影响因子：
20.3
作者：
K. Kawabata;H. Zong;Cem Meydan;Sarah Wyman;Bas J. Wouters;M. Sugita;S. Goswami;M. Albert;Winnie Yip;G. Roboz;Zhengming Chen;R. Delwel;M. Carroll;C. Mason;A. Melnick;M. Guzman
通讯作者：
M. Guzman

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

脱氢亮古丁氨基加合物的合成、晶体学和抗白血病活性。

DOI：
发表时间：
2020-10-20
期刊：
影响因子：
0
作者：
Ordóñez, Paola E;Mery, David E;Sharma, Krishan K;Nemu, Saumyadip;Reynolds, William F;Enriquez, Raul G;Burns, Darcy C;Malagón, Omar;Jones, Darin E;Guzman, Monica L;Compadre, Cesar M
通讯作者：
Compadre, Cesar M

The interaction between RUNX2 and core binding factor beta as a potential therapeutic target in canine osteosarcoma.

RUNX2 和核心结合因子 β 之间的相互作用作为犬骨肉瘤的潜在治疗靶点。

DOI：
发表时间：
2020-03
期刊：
影响因子：
0
作者：
Alegre, Fernando;Ormonde, Amanda R;Godinez, Dayn R;Illendula, Anuradha;Bushweller, John H;Wittenburg, Luke A
通讯作者：
Wittenburg, Luke A

Chemical probes and methods for single-cell detection and quantification of epichaperomes in hematologic malignancies.

用于单细胞检测和定量血液恶性肿瘤中表层体的化学探针和方法。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Merugu, Swathi;Sharma, Sahil;Kaner, Justin;Digwal, Chander;Sugita, Mayumi;Joshi, Suhasini;Taldone, Tony;Guzman, Monica L;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela