5OPR

Structure of CHK1 10-pt. mutant complex with aminopyridine LRRK2 inhibitor

Summary for 5OPR

• Entry DOI: 10.2210/pdb5opr/pdb
• Related: 5OOP 5OOR 5OOT 5OP2 5OP4 5OP5 5OP7 5OPB
• Descriptor: Serine/threonine-protein kinase Chk1, 5-[4-(morpholin-4-ylmethyl)phenyl]-3-(1-propan-2-yl-1,2,3-triazol-4-yl)pyridin-2-amine (3 entities in total)
• Functional Keywords: parkinson's disease, leucine-rich repeat kinase 2, lrrk2, checkpoint kinase 1, chk1, mutant, surrogate, kinase inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 34472.68

Authors

Dokurno, P.,Williamson, D.S.,Acheson-Dossang, P.,Chen, I.,Murray, J.B.,Shaw, T.,Surgenor, A.E. (deposition date: 2017-08-10, release date: 2017-10-25, Last modification date: 2024-01-17)

Primary citation

Williamson, D.S.,Smith, G.P.,Acheson-Dossang, P.,Bedford, S.T.,Chell, V.,Chen, I.J.,Daechsel, J.C.A.,Daniels, Z.,David, L.,Dokurno, P.,Hentzer, M.,Herzig, M.C.,Hubbard, R.E.,Moore, J.D.,Murray, J.B.,Newland, S.,Ray, S.C.,Shaw, T.,Surgenor, A.E.,Terry, L.,Thirstrup, K.,Wang, Y.,Christensen, K.V.
Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).
J. Med. Chem., 60:8945-8962, 2017

PubMed Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC values for 22 in mouse brain and kidney being 1.3 and 5 nM, respectively.

PubMed: 29023112
DOI: 10.1021/acs.jmedchem.7b01186

Experimental method

X-RAY DIFFRACTION (1.95 Å)