Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease.
Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.
Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark.
K V
KV
Christensen
Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark.
G P
GP
Smith
Vernalis (R&D) Ltd, Cambridge, United Kingdom.
D S
DS
Williamson
D000818:Animals; D015195:Drug Design; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010300:Parkinson Disease / Q000188:drug therapy*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Crystallographic surrogates; Diaminopyrimidines; Homology model; Indazoles; Pyrrolopyrimidines; Rab GTPase; Type II pneumocytes; α-Synuclein