New Molecules, Fresh Targets
A cutting-edge platform of next-generation kinase inhibitors with the potential to produce treatments for autoimmune, neuroinflammatory, oncology, and other debilitating diseases.
Our platform of next-generation small molecule kinase inhibitors includes compounds that inhibit prominent targets such as DYRK1A, LRRK2, TTK and CLK with various potency, selectivity, and blood-brain-barrier penetration profiles. This library of new chemical entities offers the potential to produce a broad range of treatments for autoimmune, inflammatory, and other debilitating diseases, including neuroinflammatory conditions like Alzheimer’s and Parkinson’s diseases. We are currently engaged in research to identify both brain penetrant and non-brain penetrant novel kinase inhibitors, which will inform the future development strategy for these next-generation therapeutic programs.
DYRK1A Inhibition in Neuroinflammation
Historically, DYRK1A has been best-known for its association with Down syndrome, where DYRK1A is overexpressed. Recent research increasingly points to a link between DYRK1A overexpression and neurodegeneration, including early-onset Alzheimer’s disease, which is frequently observed in Down syndrome patients. Approximately 20% of Down syndrome patients over the age of 45 have dementia, which correlates with increased mortality.
The association of DYRK1A with neurodegeneration is manyfold: DYRK1A directly phosphorylates tau, which contributes to the formation of pathologic neurofibrillary tangles, a hallmark of Alzheimer’s disease. DYRK1A also regulates splicing and increases the ratio of 3R-tau over 4R-tau, which is observed in the brain tissue of Down syndrome and Alzheimer’s disease patients. Furthermore, DYRK1A was recently shown to increase the cleavage of the amyloid precursor protein, leading to the formation of amyloid plaques. Thus, the formation of neurofibrillary tangles and amyloid plaques both converge on the DYRK1A target.
In addition to the histological aspect of neurodegeneration, DYRK1A may also play a role in neuroinflammation through the regulation of innate immunity. Chronic inflammation in the central nervous system is characteristic of neurodegeneration, with the involvement of cytokines IL-1, TNF-α, and IFN-γ, all of which can be suppressed by inhibition of DYRK1A. Inhibition of DYRK1A and the subsequent reduction in tau phosphorylation, amyloid plaque formation, and neuroinflammation may present a first-of-a-kind, disease-modifying treatment for neurodegeneration in Alzheimer’s disease, which affects 47 million people worldwide, the most common cause of dementia, and a leading cause of mortality and morbidity in aging populations.
LRRK2 Inhibition in Neuroinflammation
LRRK2 (Leucine-Rich Repeat Kinase 2) is a dual serine/threonine kinase and GTPase with strong genetic links to Parkinson’s Disease (PD), which impacts over 820,000 patients in the U.S. The most prevalent mutation in the LRRK2 kinase domain (G2019S) is associated with approximately 4% of familial and 1% of sporadic PD cases in the U.S., with approximately 8,000 mutant LRRK2 carriers.
Pathobiology of PD involves the region-specific loss of dopaminergic neurons. Early-onset symptoms include tremors and small changes in a person’s movements, posture, and walking. While symptom management therapies are available, there is a tremendous unmet need for disease-modifying neuroprotective therapies that would delay disease progression.
Our next-generation kinase inhibitor platform includes molecules that inhibit both LRRK2 and LRRK2(G2019S) kinase activity, or selectively inhibit only the mutant form LRRK2(G2019S). Both approaches may present novel and differentiated treatment options for PD.
Sources:
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