DFG-out inhibitors of Abl-kinases to treat PML

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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.