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）：抑制酶治疗剂是一家临床阶段，生物制药公司，已开发出一种宿主针对性的作用机理，以治疗与艾滋病相关的和药物诱导的进行性促进性多灶性多焦点白血病（PML）。 PML是中枢神经系统的一种脱髓鞘疾病，在1980年代中期始于HIV流行时代之前，很少在临床上看到。在流行病的高峰期，PML的发生率上升了20倍，其中5％的患者患有疾病折磨的临床艾滋病。实际上，PML成为与艾滋病流行有关的第一个临床综合征。随着免疫抑制单克隆抗体（MAB）的引入，PML对大多数MAB疗法越来越关注，除了艾滋病患者中发生的IS是发生。 PML是由多瘤病毒JC致病性转化引起的，多瘤病毒JC是一种持续感染成年人的病毒。但是，当患者免疫功能低下时，JC经历了基因组重排，将病毒转化为一种致病形式，用于脑少突胶质细胞，并将其转化为脑部。一旦感染大脑，感染就会裂解，并导致严重的痴呆，肢体功能和死亡的丧失。尽管有许多临床努力，但尚未确定多重抗病毒，这在很大程度上是由于稀疏的药物测试景观而造成的 JC的允许非人类宿主。抑制酶治疗方法采取了不同的方法，并确定了可能破坏宿主细胞中JC繁殖的宿主目标。该公司已经证明，宿主ABL激酶抑制会破坏JC多瘤病毒的进入，使用抗癌剂Gleevec作为原理证明药物来定义作用机理。然而，格莱维克无法达到人类的有效集中度以实现这一效果。提议利用硅和SAR分析的初始结果，以开发出更有效的ABL激酶抑制剂。初步结果确定了推定的代理和设计原理，该原则能够通过SAR分析成功地识别识别。