Protein Kinase Targeted Therapeutics (26087)

A validated novel compound and medicinal chemistry refinement for bioavailable small molecule inhibitors of protein kinases or protein kinase-mediated cellular stress response pathways.

ADVANTAGES: A small molecule p38α MAPK inhibitor presents significant therapy potential for neurodegenerative diseases and other CNS disorders where proinflammatory cytokine overproduction is a component, such as Alzheimers (AD) and related indications, Parkinson’s, multiple sclerosis, and traumatic brain injury.

SUMMARY: Kinases are attractive drug discovery targets due to their involvement in signal amplification pathways that modulate cellular response to disease-relevant stressors. Targeting kinases involved in gene expression and with substrate Km values between 1-20 micromolar raises the potential for development of small molecule inhibitors with extended pharmacodynamic effects that exceed the time of peak drug concentration in tissues. p38α MAPK is a well- established drug discovery target for altering proinflammatory cytokine overproduction cascades in peripheral tissue disorders. The current state of the art for p38α MAPK inhibitor development suggests there is no mechanism-of-action-based toxicity related to targeting p38α MAPK, but side effects are compound- or chemotype-specific. Increasing evidence suggests p38α MAPK is also an important regulator of proinflammatory cytokine levels in the CNS, raising the possibility that the kinase may be a drug target for CNS disorders where cytokine overproduction contributes. Activated p38α MAPK is observed in human AD brain tissue and implicated in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors.

Currently available p38α MAPK drugs inhibitors have inadequate adsorption and metabolism potential contributing to lack of efficacy or toxicity in vivo or have insufficient blood-brain barrier penetrance as therapeutics for neurodegenerative disorders. A CNS kinase inhibitor discovery platform was developed with molecular properties having good oral bioavailability, blood-brain barrier penetrance, metabolic stability, and non-toxicity in in vivo rodent models. Furthermore, significant in vitro inhibition selectivity for only the p38α MAPK isoform was realized.

One p38α MAPK inhibitor (compound 069A), demonstrates efficacy after oral administration in an established AD-relevant mouse model that involves ICV infusion of Aβ, to induce proinflammatory cytokine up-regulations, synaptic dysfunction and hippocampal behavior deficits. Low dose (2.5 mg/kg) administration of the compound for 2 weeks (21 days after Aβ infusion start) significantly reduced the overproduction of IL-1β, TNFα and S100B cytokines back toward basal (Figure 1). Treatment also attenuated loss of synaptophysin and ameliorated Y-maze behavior deficit (Figure 2). The results demonstrate the effectiveness of the p38α MAPK inhibitor 069A in the AD-relevant model and support the importance of targeting this protein kinase pathway for CNS disorders.

STATUS: A platform for discovery and rapid refinement is established. An efficient synthetic scheme for the 069A lead p38α MAPK inhibitor and analogs has been developed and patent applications filed. Current efforts focus on therapeutic index improvement in animal models and in vivo target validation.

REFERENCE: Journal of Neuroinflammation (2007), 4: 21

Type of Offer: Licensing

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