Elucidating the Role of Binding Kinetics in the Development of Abl Kinase Drug Resistance

阐明结合动力学在 Abl 激酶耐药性发展中的作用

• 批准号: 10230830
• 负责人: Aziz Mohammedi Rangwala
• 金额: $ 3.82万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-17 至 2025-02-16
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10230830
• 关键词: Achievement; Address; Affect; Affinity; BCR gene; Binding; Binding Sites; Biochemical; Biological Assay; Biological Models; Cell Survival; Cellular Assay; Chronic Myeloid Leukemia; Clinical; Crystallization; Data; Development; Disease; Dissociation; Distant; Dose; Drug Design; Drug Kinetics; Drug Receptors; Drug Targeting; Drug resistance; Effectiveness; Environment; Enzymes; Equilibrium; Exhibits; Gatekeeping; Genes; Goals; Human body; Hydrogen Bonding; Imatinib; In Vitro; Inflammatory; Kinetics; Knowledge; Libraries; Ligand Binding; Ligands; Malignant Neoplasms; Measures; Molecular Conformation; Mutation; Oncogenes; Oncogenic; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phosphotransferases; Process; Protein Family; Protein Kinase; Proteins; Proto-Oncogene Proteins c-abl; Recovery; Regimen; Relapse; Research; Resistance; Resistance development; Role; Schedule; Secondary to; Seminal; Series; Signal Transduction; Specificity; Structure; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; bcr-abl Fusion Proteins; cancer cell; cellular transduction; clinical efficacy; clinically relevant; combat; design; dosage; drug action; drug discovery; drug efficacy; effective therapy; experimental study; improved; in vivo; inhibitor/antagonist; insight; interest; kinase inhibitor; leukemogenesis; mortality; mutant; novel; pharmacodynamic model; preservation; residence; resistance mutation; response; small molecule; small molecule inhibitor; success; targeted treatment; therapy resistant; treatment strategy

PROJECT SUMMARY The development of small molecule inhibitors has revolutionized targeted therapeutics, especially in the field of protein kinases. However, pharmaceutical development continues to be plagued by two problems: (i) designing specific drugs with limited off-target toxicity and (ii) combating the occurrence of resistance mutations in the target of interest. The role of binding kinetics, referring to a ligand’s association and dissociation rate to its target, are underexplored and underexploited in addressing these issues. In the non-equilibrium environment of the human body, drug on- and off-rates have proven to be superior optimization parameters for candidate compounds than the traditional IC50 and KD metrics. Furthermore, mutations that reduce drug residence time, defined as how long a drug stays bound to its target, can presumably confer resistance to therapy. Imatinib, the seminal achievement of rational drug design, inhibits the BCR-Abl oncoprotein and has reduced the mortality rate for chronic myelogenous leukemia by 80%. Imatinib’s specificity for Abl kinase is due to its conformational selectivity, and its success has sparked intense efforts to discover specific inhibitors of kinases dysregulated in cancer and inflammatory disease. Despite its clinical success, relapse to imatinib therapy due to resistance mutations is common, and a fundamental understanding of how mutations distant from the ligand binding site cause resistance continues to elude us. We have preliminarily identified a series of patient-derived resistance mutations that paradoxically show no change in equilibrium affinity for imatinib. We have also validated that the Abl N368S mutant causes imatinib resistance by increasing drug dissociation rate. Therefore, I propose using these Abl kinase mutations as a model system to explore how binding kinetics affect ligand specificity, potency, and efficacy. My central hypothesis is that altered inhibitor binding or dissociation kinetics could cause resistance independent of inhibitor affinity. I will explore this hypothesis by measuring the effects of Abl kinase mutations on drug residence time and efficacy and by defining the conformational changes of the Abl N368S substitution. Through these studies, I will determine the structural mechanism of “kinetic resistance” mutations, a novel type of drug resistance which I believe extends throughout the kinome. I will also elucidate key structural factors in the conformational exchange of Abl kinase and the imatinib unbinding process. In addition, I will provide insight into how prolonging in vivo drug action through slow dissociation rates can be applied to develop drugs with minimal off-target toxicity. The contributions from this proposal are significant because they will validate altered binding kinetics as both a novel mechanism of drug resistance in a highly-therapeutically relevant protein family and as a viable strategy to improve drug specificity.

项目总结