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

• 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
• 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

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（由申请人提供）：慢性髓性白血病（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。临床复发是常见的，并对成功的酪氨酸激酶抑制剂（TKI）治疗提出了极大的挑战。ABL激酶结构域的突变是伊马替尼耐药（IMR）的主要机制。第二代BCR/ABL抑制剂尼洛替尼和达沙替尼可有效抑制IMR变体，但对看门突变体T315 I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守门突变进行了表征，并发现用大的疏水性残基取代守门苏氨酸可以通过稳定活性状态期间组装的“疏水性脊柱”来激活激酶。我们提出下一代抑制剂应该是破坏活性态的组装，稳定非活性态。这项工作使我们开发了第三代ABL激酶抑制剂，AP 24163，AP 24534和GNF-5。鉴于我们对第一代和第二代抑制剂的数据和经验，很可能对第三代抑制剂也会产生耐药性。最近，我们已经证明，第三代抑制剂AP 24163-临床药物AP 24534的母体化合物-特异性选择ABL激酶中的化合物突变，对此我们没有任何治疗选择。该提案旨在鉴定针对第三代临床抑制剂AP 24534（Ponatinib）的耐药突变。化合物突变主要来自ABL激酶的变构位点。本研究旨在研究化合物突变产生耐药性的机制，并开发小分子变构抑制剂靶向变构位点的策略。为此，我们已经确定了一个独特的疏水模块-疏水环带-支配激酶调节。我们预期，这种疏水基序的详细表征将帮助我们开发新的变构抑制剂，其可以与ATP竞争性抑制剂组合使用以抑制所有形式的抗性突变。