7BKO

Crystal structure of CHK1 complex with compound 9

Summary for 7BKO

• Entry DOI: 10.2210/pdb7bko/pdb
• Related: 7bjd 7bje 7bjh 7bjj 7bjm 7bjo 7bjr 7bjx 7bk1 7bk2 7bk3
• Descriptor: Serine/threonine-protein kinase Chk1, 1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: parkinson's disease, leucine-rich repeat kinase 2, lrrk2, checkpoint kinase 1, chk1, mutant, surrogate, kinase inhibitor, sbdd, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34283.28

Authors

Baker, L.M.,Surgenor, A.E.,Williamson, D.S. (deposition date: 2021-01-16, release date: 2021-07-07, Last modification date: 2024-01-31)

Primary citation

Williamson, D.S.,Smith, G.P.,Mikkelsen, G.K.,Jensen, T.,Acheson-Dossang, P.,Badolo, L.,Bedford, S.T.,Chell, V.,Chen, I.J.,Dokurno, P.,Hentzer, M.,Newland, S.,Ray, S.C.,Shaw, T.,Surgenor, A.E.,Terry, L.,Wang, Y.,Christensen, K.V.
Design and Synthesis of Pyrrolo[2,3- d ]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.
J.Med.Chem., 64:10312-10332, 2021

PubMed Abstract: Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2)-2-Methylpyrrolidin-1-yl derivative (LRRK2 G2019S c 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of gave the 2-[(1,3-dimethyl-1-pyrazol-4-yl)amino] derivative . Optimization of afforded diastereomeric oxolan-3-yl derivatives and , which demonstrated a favorable PK profile, although they displayed species disconnects in the PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds and demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.

PubMed: 34184879
DOI: 10.1021/acs.jmedchem.1c00720

Experimental method

X-RAY DIFFRACTION (2.3 Å)