Bidentate-binding modulators of LRRK2 and JNK kinases

Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (MI), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strate...

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Bibliographic Details
Main Authors Feng Yangbo, Lo Grasso Philip
Format Patent
LanguageEnglish
Published 26.12.2017
Subjects
CHEMISTRY
HETEROCYCLIC COMPOUNDS
HUMAN NECESSITIES
HYGIENE
MEDICAL OR VETERINARY SCIENCE
METALLURGY
ORGANIC CHEMISTRY
PEPTIDES
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
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Summary:Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (MI), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families.
Bibliography:Application Number: US201414893615