8E80

Structure of LRRK2-CHK1 10-pt. mutant complex with heteroaryl-1H-indazole LRRK2 inhibitor 14

Summary for 8E80

• Entry DOI: 10.2210/pdb8e80/pdb
• Descriptor: Serine/threonine-protein kinase Chk1, 2-[(1r,4r)-2-{(6P)-6-[(6M)-6-(1H-pyrazol-5-yl)-1H-indazol-1-yl]pyrimidin-4-yl}-2-azabicyclo[2.1.1]hexan-4-yl]propan-2-ol (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34495.67

Authors

Palte, R.L. (deposition date: 2022-08-25, release date: 2023-02-22, Last modification date: 2023-10-25)

Primary citation

Candito, D.A.,Simov, V.,Gulati, A.,Kattar, S.,Chau, R.W.,Lapointe, B.T.,Methot, J.L.,DeMong, D.E.,Graham, T.H.,Kurukulasuriya, R.,Keylor, M.H.,Tong, L.,Morriello, G.J.,Acton, J.J.,Pio, B.,Liu, W.,Scott, J.D.,Ardolino, M.J.,Martinot, T.A.,Maddess, M.L.,Yan, X.,Gunaydin, H.,Palte, R.L.,McMinn, S.E.,Nogle, L.,Yu, H.,Minnihan, E.C.,Lesburg, C.A.,Liu, P.,Su, J.,Hegde, L.G.,Moy, L.Y.,Woodhouse, J.D.,Faltus, R.,Xiong, T.,Ciaccio, P.,Piesvaux, J.A.,Otte, K.M.,Kennedy, M.E.,Bennett, D.J.,DiMauro, E.F.,Fell, M.J.,Neelamkavil, S.,Wood, H.B.,Fuller, P.H.,Ellis, J.M.
Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1 H -Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease.
J.Med.Chem., 65:16801-16817, 2022

PubMed Abstract: Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp-sp cross-coupling technologies. This resulted in the discovery of a unique sp-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, , demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.

PubMed: 36475697
DOI: 10.1021/acs.jmedchem.2c01605

Experimental method

X-RAY DIFFRACTION (1.49 Å)