Mechanisms of drug resistance in Myeloproliferative neoplasms treated with JAK2 i

JAK2 i 治疗骨髓增生性肿瘤的耐药机制

基本信息

批准号：
8445600
负责人：
Mohammad Azam
金额：
$ 18.21万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445600
关键词：
Accounting Autoimmune Process Binding Biochemical Biological Assay CEP 701 Chemicals Chronic Myeloid Leukemia Clinical Clinical Trials Complement Computer Simulation Constitutional Symptom Coupled Data Development Diagnosis Disease Drug Design Drug Targeting Drug resistance FDA approved Frequencies Future Gleevec Goals Hematopoietic Neoplasms Hematopoietic stem cells Hemorrhagic Thrombocythemia Immune In Vitro Inflammatory JAK2 gene Lead Mediating Modeling Molecular Conformation Mus Mutagenesis Mutation Myeloproliferative disease Oncogenes Pathogenesis Patients Pattern Pharmaceutical Preparations Phase Phosphotransferases Point Mutation Polycythemia Vera Preclinical Drug Evaluation Primary Myelofibrosis Protein Kinase Inhibitors Psoriasis Regulation Research Resistance Resistance development Rheumatoid Arthritis Role Sampling Somatic Mutation Spleen Structural Models Structure-Activity Relationship Sum Surveys Testing Therapeutic Therapeutic Intervention Tyrosine Kinase Inhibitor Validation Variant Xenograft Model bcr-abl Fusion Proteins cancer therapy chemical genetics combat improved in vivo inhibitor/antagonist insight kinase inhibitor mutant next generation novel protein kinase inhibitor public health relevance resistance mechanism response screening small molecule success therapeutic development therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The expression of constitutively active JAK2 kinase in hematopoietic stem cells is sufficient to induce myeloproliferative neoplasms (MPNs) in mice paved the way for developing JAK2-targeted therapies. Recent clinical success of JAK2 inhibitors (INCB018424 and TG101348) in the treatment of MPN patients are promising, and most likely these two clinical agents will be approved by FDA for the treatment of JAK2 mediated disorders. Given the structural plasticity in kinases and emergence of resistance to kinase inhibitor therapy we anticipate that resistance to JAK2 inhibitors will develop as well. Additionally, our current understandings of JAK2 regulatory mechanisms are speculative. For instance, how somatic mutations activate the kinase is not fully understood that limits us to develop efficient therapeutic development. Mutagenesis studies coupled with in silico structural modeling provide greater structural-functional insights, patient management and drug design. Toward this end, we propose to identify the drug resistant mutations for JAK2 clinical inhibitors to understand the mechanisms of drug resistance and JAK2 regulatory mechanisms. Our preliminary data suggests that the frequency of resistance against INCB018424 is higher as compared to TG101348 suggesting their selectivity for distinct kinase conformations. We hypothesize that these inhibitors will select for different constellation of mutations and may complement each other to suppress the development of resistance. In this study, we propose to perform mutational studies coupled with biochemical and structural characterization to understand the mechanisms of drug resistance and JAK2 regulation that will help us patient diagnosis, drug design and developing strategies to combat clinical resistance.

描述（由申请人提供）：造血干细胞中组成型活性JAK2激酶的表达足以在小鼠中诱导骨髓增殖性肿瘤（MPN），为开发JAK2靶向疗法铺平了道路。最近 JAK2 抑制剂（INCB018424 和 TG101348）在治疗 MPN 患者方面取得的临床成功是有希望的，并且这两种临床药物很可能将被 FDA 批准用于治疗 JAK2 介导的疾病。鉴于激酶的结构可塑性和对激酶抑制剂治疗的耐药性的出现，我们预计对 JAK2 抑制剂的耐药性也会发展。此外，我们目前对 JAK2 调控机制的理解是推测性的。例如，体细胞突变如何激活激酶尚不完全清楚，这限制了我们开发有效的治疗方法。诱变研究与计算机结构建模相结合，提供了更深入的结构功能见解、患者管理和药物设计。为此，我们建议鉴定JAK2临床抑制剂的耐药突变，以了解耐药机制和JAK2调控机制。我们的初步数据表明，与 TG101348 相比，对 INCB018424 的耐药频率更高，表明它们对不同激酶构象的选择性。我们假设这些抑制剂将选择不同的突变群，并且可能相互补充以抑制耐药性的发展。在这项研究中，我们建议进行突变研究以及生化和结构表征，以了解耐药性和 JAK2 调节的机制，这将有助于我们的患者诊断、药物设计和制定对抗临床耐药性的策略。