Jaclyn Louise Henderson

Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinsons disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinsons disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.

Discovery of hydroxamate bioisosteres as KAT II inhibitors with improved oral bioavailability and pharmacokinetics

A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere. Triazolinones or triazoles have proven to be effective replacements with significantly improved pharmacokinetics including reduced clearance and increased bioavailability. An X-ray crystal structure of an inhibitor bound in KAT II confirms that the irreversible binding to the co-factor is maintained and that the heterocycles make productive hydrogen bonds to the arginine-399.

Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of autosomal dominant Parkinson’s disease (PD), accounting for approximately 1% of “sporadic” and 4% of familial cases. These mutations either lead directly to an increased kinase activity (G2019S and I2020T are in the kinase activation loop) or to a reduced GTPase activity (R1441C/G and Y1699C), that in turn positively regulate kinase activity. The physiological substrate of the LRRK2 kinase has yet to be definitively identified, yet autophosphorylation is emerging as a relatively robust measure of its activity. LRRK2 has been implicated in a number of diverse cellular processes such as vesicular trafficking, microtubule dynamics, protein translation control, inflammation, and immune function, all of which have been linked to PD. LRRK2 is a large, multi-domain protein; a thorough understanding of the protein domain organization and identification of interacting partners is important to determine the underlying mechanism of LRRK2. Substantial recent effort has been directed towards identifying potent LRRK2 kinase inhibitors, from the repurposed kinase inhibitors to the first through third generation of LRRK2-focused kinase inhibitors, from a range of chemotypes, which are now providing researchers with new tools to better interrogate LRRK2 function.

Chapter Four - Development of LRRK2 Kinase Inhibitors for Parkinson's Disease

Abstract Parkinsons disease (PD) is the most common movement disorder and the second most common neurodegenerative disorder after Alzheimers disease. The etiology of PD is complex but the most common phenotype is the loss of dopaminergic neurons of the substantia nigra leading to the clinical symptoms of bradykinesia, resting tremors, rigidity, and postural instability. The most common genetic cause of autosomal dominant PD is mutations in leucine-rich repeat kinase 2 (LRRK2) which accounts for 1% of sporadic and 4% of familial cases. The G2019S mutation is the most common in LRRK2 and occurs in the DYG motif of the kinase domain, where it appears to increase its kinase activity. Consequently, a great deal of effort has been directed toward identifying potent LRRK2 kinase inhibitors with a biopharmaceutical profile congruent with clinical evaluation and this report summarizes efforts in this regard.