Brickell Bio’s novel kinase inhibitor platform is a library of new chemical entities including next-generation DYRK1A inhibitors and other molecules that specifically inhibit LRRK2, TTK, and CLK kinases. A number of these molecules have the potential to penetrate the blood-brain-barrier, presenting the potential to address high unmet need neuroinflammatory conditions.
In addition to being upregulated in Down’s Syndrome, DYRK1A is associated with phosphorylating tau and promoting the cleavage of amyloid precursor protein, which are associated with the pathogenesis of Alzheimer’s Disease and Pick Disease. A brain-penetrating DYRK1A inhibitor can potentially provide a novel therapeutic option for these diseases.
LRRK2 (Leucine Rich Repeat Kinase 2) is a dual serine/threonine kinase and GTPase with strong genetic links to Parkinson’s Disease (PD). Mutations in its kinase domain, the most prevalent of which is G2019S, are associated with approximately 5% of familial PD cases in the US. Brickell’s molecule library includes molecules that inhibit both LRRK2 and LRRK2(G2019S) kinase activity, and may include brain-penetrating candidates for the treatment of Parkinson’s Disease.
Beyond neuroinflammation, Brickell is also exploring the opportunities of peripherally acting novel kinase inhibitors for CLK, TKK and LRRK2 in additional therapeutics areas.
Brickell plans to select lead candidates from the kinase inhibitor platform for IND-enabling studies to potentially treat neuroinflammatory and other debilitating conditions in 2022, followed by additional preclinical studies to further inform the future indication and development strategy for these programs.
Sources
1. Wegiel, J., Gong, C.-X. & Hwang, Y.-W. The role of DYRK1A in neurodegenerative diseases. FEBS J. 278, 236–245 (2011).
2. Kimura, R. et al. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease. Hum. Mol. Genet. 16, 15–23 (2007).
3. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol 2020 162. 2020;16(2):97-107.
4. Dächsel JC, Farrer MJ. LRRK2 and Parkinson Disease. Arch Neurol. 2010;67(5):542-547.
