Improved therapeutic approaches for hematological disorder treated with tyrosine

酪氨酸治疗血液疾病的改进治疗方法

基本信息

批准号：
8463476
负责人：
Mohammad Azam
金额：
$ 29.84万
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：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463476
关键词：
Accounting Allosteric Site Animal Model Area Binding Biochemical Catalytic Domain Characteristics Chemicals Chronic Myeloid Leukemia Clinic Clinical Clinical Trials Computer Simulation Dasatinib Data Development Dimerization Disease Disease remission Docking Drug Design Drug resistance Epidermal Growth Factor Receptor Evolution Family Future Gatekeeping Generations Goals Hematologic Neoplasms Hematological Disease Hematopoietic stem cells Imatinib In Vitro Lobe Mediating Modeling Molecular Molecular Conformation Mutagenesis Mutation PDGFRA gene PDGFRB gene Parents Patients Pattern Pharmaceutical Preparations Phosphotransferases Play Point Mutation Protein Kinase Protein Kinase Inhibitors Protein Tyrosine Kinase Proteins Regulation Relapse Research Residual Tumors Resistance Resistance development Role Running Sampling Specificity Structural Models Structure Testing Therapeutic Therapeutic Agents Threonine Tyrosine Tyrosine Kinase Inhibitor Variant Vertebral column Work base bcr-abl Fusion Proteins cancer therapy chemical genetics clinically relevant combat design experience improved inhibitor/antagonist kinase inhibitor mouse model mutant next generation novel protein kinase inhibitor resistance mechanism response small molecule src Homology Region 2 Domain success theories treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder and currently treated by BCR/ABL tyrosine kinase inhibitors such as Imatinib, Dasatinib and Nilotinib. Clinical relapses are common and pose great challenge for successful tyrosine kinase inhibitor (TKI) therapy. Mutations in the ABL kinase domain are the principal mechanism of Imatinib resistance (IMR). The second-generation BCR/ABL inhibitors Nilotinib and Dasatinib effectively inhibit IMR variants, but are ineffective against the gatekeeper mutant, T315I. Mutation of the gatekeeper residue mediates broad-spectrum drug resistance and is a common mechanism of resistance across tyrosine kinase inhibitor therapy such as ABL, KIT, SRC, PDGFRA, PDGFRB and EGFR. Recently, we have characterized the gatekeeper mutations in these kinases and discovered that the substitution of a bulky hydrophobic residue for the gatekeeper threonine activates the kinase by stabilizing the "hydrophobic spine" assembled during the active state. We proposed that the next-generation inhibitor should disrupt the assembly of active state and stabilize the inactive state. This work has led us to develop third-generation ABL kinase inhibitors, AP24163, AP24534 and GNF-5. Given our data and experiences with first and second-generation inhibitors, it is likely that resistance to third-generation inhibitors will develop as well. Recently we have shown that the third-generation inhibitor AP24163 - the parent compound of the clinical agent AP24534 - specifically selects for compound mutations in ABL kinase to which we do not have any therapeutic option. This proposal is aimed to identify drug resistant mutations against third generation clinical inhibitors AP24534 (Ponatinib). Compound mutations are mostly presented from the allosteric sites of the ABL kinase. This proposal is aimed to study the mechanism employed by the compound mutations to confer resistance and to develop strategies to target the allosteric sites by small molecule allosteric inhibitors. Towards this end we have identified a unique hydrophobic module- hydrophobic girdle-that governs kinase regulation. We anticipate that a detail characterization of this hydrophobic-motif will help us in developing new allosteric inhibitors tha can be used in combination with ATP- competitive inhibitors to suppress all forms resistant mutations.

描述（申请人提供）：慢性粒细胞白血病（CML）是一种造血干细胞疾病，目前采用 BCR/ABL 酪氨酸激酶抑制剂（如伊马替尼、达沙替尼和尼洛替尼）治疗。临床复发很常见，这对成功的酪氨酸激酶抑制剂（TKI）治疗提出了巨大的挑战。 ABL 激酶结构域突变是伊马替尼耐药 (IMR) 的主要机制。第二代BCR/ABL抑制剂尼罗替尼和达沙替尼可有效抑制IMR变异体，但对看门人突变体T315I无效。看门人残基突变介导广谱耐药性，是酪氨酸激酶抑制剂治疗（如 ABL、KIT、SRC、PDGFRA、PDGFRB 和 EGFR）的常见耐药机制。最近，我们对这些激酶中的看门突变进行了表征，并发现用大的疏水残基替代看门苏氨酸可以通过稳定活性状态期间组装的“疏水脊柱”来激活激酶。我们提出下一代抑制剂应该破坏活性状态的组装并稳定非活性状态。这项工作促使我们开发了第三代 ABL 激酶抑制剂 AP24163、AP24534 和 GNF-5。鉴于我们对第一代和第二代抑制剂的数据和经验，对第三代抑制剂的耐药性也可能会出现。最近，我们已经证明，第三代抑制剂 AP24163（临床药物 AP24534 的母体化合物）专门选择 ABL 激酶中的化合物突变，而我们对此没有任何治疗选择。该提案旨在识别针对第三代临床抑制剂 AP24534（Ponatinib）的耐药突变。复合突变主要来自 ABL 激酶的变构位点。该提案旨在研究复合突变赋予耐药性的机制，并制定小分子变构抑制剂靶向变构位点的策略。为此，我们确定了一种独特的疏水模块——疏水带——控制激酶调节。我们预计，这种疏水基序的详细表征将有助于我们开发新的变构抑制剂，该抑制剂可与 ATP 竞争性抑制剂联合使用，以抑制所有形式的耐药突变。