DFG-out inhibitors of Abl-kinases to treat PML

Abl 激酶的 DFG-out 抑制剂治疗 PML

• 批准号: 8586614
• 负责人: Milton H. Werner
• 金额: $ 30万
• 依托单位: INHIBIKASE THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586614
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affinity; Animal Model; Antineoplastic Agents; Antiviral Agents; Autoimmune Diseases; Binding; Biological Products; Bone Marrow; Brain; Cell Culture Techniques; Cells; Cessation of life; Clinical; Communicable Diseases; Computer Simulation; Contracts; Cultured Cells; DNA Sequence Rearrangement; DNA Viruses; Data; Dementia; Disease; Down-Regulation; Epidemic; Failure; Genomics; Gleevec; HIV; Height; Human; Immunocompromised Host; Immunosuppressive Agents; Infection; Investigation; JC Virus; Kidney; Lead; Libraries; Limb structure; Lytic; Malignant Neoplasms; Metabolic; Metabolism; Monoclonal Antibodies; Monoclonal Antibody Therapy; Oligodendroglia; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphotransferases; Polyomavirus; Progressive Multifocal Leukoencephalopathy; Relative (related person); Reproduction; Risk; Risk Factors; Rosa; Site; Staging; Structure-Activity Relationship; Syndrome; Testing; Therapeutic; Toxic effect; Tropism; Viral; Virus; Virus Diseases; analog; central nervous system demyelinating disorder; clinical Diagnosis; clinical efficacy; comparative; compound 30; design; drug discovery; immunosuppressed; inhibitor/antagonist; kinase inhibitor; meetings; novel; novel strategies; pre-clinical; prevent; public health relevance; receptor; research clinical testing

DESCRIPTION (provided by applicant): Inhibikase Therapeutics is a clinical stage, biopharmaceutical company that has developed a host- targeted mechanism of action to treat AIDS-related and drug-induced progressive multifocal leukoencephalopathy (PML). PML is a demyelinating disease of the central nervous system and was rarely seen clinically until the era of the HIV epidemic began in the mid-1980s. During the height of the epidemic, the rate of PML occurrence rose 20-fold, with 5% of patients with a diagnosis of clinical AIDS afflicted by the disease. Indeed, the PML became the first clinical syndrome associated with the AIDS epidemic. With the introduction of immunosuppressive monoclonal antibodies (mAb), PML has become a growing concern for most mAb therapies in addition to is occurrence in patients with AIDS. PML results from pathogenic conversion of the polyomavirus JC, a virus that persistently infects adult humans. When a patient becomes immunocompromised, however, JC undergoes a genomic rearrangement, converting the virus to a pathogenic form with tropism for brain oligodendrocytes. Once infecting brain, the infection is lytic and leads to severe dementia, loss of limb function and death. Despite numerous clinical efforts, no polyoma antiviral has been identified, a failure that is largely due to the sparse testing landscape for drug discovery and no permissive non- human host for JC. Inhibikase Therapeutics has taken a different approach and identified host-targets that can disrupt JC reproduction in host cells. The Company has demonstrated that host Abl-kinase inhibition can disrupt JC polyomavirus entry, using the anti-cancer agent Gleevec as a proof-of-principle drug substance to define the mechanism of action. Gleevec, however, cannot reach the effective concentration in humans to achieve this effect. It is proposed to capitalize on the outcomes of an initial in silico and SAR analysis to develop a more potent Abl-kinase inhibitor. Preliminary results identify a putative agent and the design principle that enables a successful pathway to lead identification through SAR analysis.

描述（由申请人提供）：Inhibikase Therapeutics 是一家临床阶段的生物制药公司，该公司开发了一种宿主靶向作用机制，用于治疗 AIDS 相关和药物诱导的进行性多灶性白质脑病 (PML)。 PML 是一种中枢神经系统脱髓鞘疾病，直到 20 世纪 80 年代中期 HIV 流行时代开始之前，临床上很少见。在流行高峰期间，PML的发生率上升了20倍，5%的患者被诊断为临床艾滋病，患有该疾病。事实上，PML 成为第一个与艾滋病流行相关的临床综合征。随着免疫抑制单克隆抗体 (mAb) 的引入，除 AIDS 患者中发生的 PML 外，PML 已成为大多数 mAb 疗法日益关注的问题。 PML 是多瘤病毒 JC 致病性转化的结果，JC 是一种持续感染成年人的病毒。然而，当患者免疫功能低下时，JC 会发生基因组重排，将病毒转化为对脑少突胶质细胞具有趋向性的致病形式。一旦感染大脑，感染就会溶解，导致严重痴呆、肢体功能丧失和死亡。尽管进行了大量的临床努力，但尚未发现多瘤抗病毒药物，这一失败很大程度上是由于药物发现的测试环境稀疏，而且没有发现任何药物。 JC 的许可非人类宿主。 Inhibikase Therapeutics 采用了不同的方法，并确定了可以破坏宿主细胞中 JC 繁殖的宿主靶点。该公司已经证明，宿主 Abl 激酶抑制可以破坏 JC 多瘤病毒的进入，使用抗癌剂格列卫作为原理验证药物来定义作用机制。然而，格列卫在人体中无法达到达到这种效果的有效浓度。建议利用初步计算机模拟和 SAR 分析的结果来开发更有效的 Abl 激酶抑制剂。初步结果确定了假定的代理和设计原则，从而能够成功地通过 SAR 分析引导识别。