DFG-out inhibitors of Abl-kinases to treat PML

描述（由申请人提供）：Inhibikase Therapeutics是一家临床阶段的生物制药公司，开发了一种针对宿主的作用机制，用于治疗艾滋病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，在20世纪80年代中期HIV流行时代开始之前，临床上很少见到。在疫情最严重的时期，PML的发病率上升了20倍，5%的临床诊断为艾滋病的患者患有这种疾病。事实上，PML成为了第一个与艾滋病流行相关的临床综合症。随着免疫抑制单克隆抗体（mAb）的引入，除了在艾滋病患者中发生外，PML已成为大多数mAb疗法越来越关注的问题。PML是由多瘤病毒JC的致病性转化引起的，多瘤病毒JC是一种持续感染成人的病毒。然而，当患者免疫功能受损时，JC经历基因组重排，将病毒转化为具有脑少突胶质细胞倾向的致病性形式。一旦感染大脑，感染是溶解性的，并导致严重的痴呆，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，这在很大程度上是由于药物发现的测试环境很少，而且没有

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.