5U6I

Discovery of MLi-2, an Orally Available and Selective LRRK2 Inhibitor that Reduces Brain Kinase Activity

Summary for 5U6I

• Entry DOI: 10.2210/pdb5u6i/pdb
• Descriptor: Mitogen-activated protein kinase 1, 3-[2-(morpholin-4-yl)pyridin-4-yl]-5-[(propan-2-yl)oxy]-1H-indazole, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mli-2, lrrk2, kinase inhibitor, kinase selectivity, parkinson's disease, transferase, serine/ threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P63086
• Total number of polymer chains: 1
• Total formula weight: 43084.36

Authors

Scott, J.D.,DeMong, D.E.,Fell, M.J.,Mirescu, C.,Basu, K.,Greshock, T.J.,Morrow, J.A.,Xiao, L.,Hruza, A.,Harris, J.,Tiscia, H.E.,Chang, R.K.,Embrey, M.W.,McCauley, J.A.,Li, W.,Lin, S.,Liu, H.,Dai, X.,Baptista, M.,Agnihotri, G.,Columbus, J.,Mei, H.,Poirier, M.,Zhou, X.,Lin, Y.,Yin, Z.,Sanders, J.M.,Drolet, R.E.,Kern, J.T.,Kennedy, M.E.,Parker, E.M.,Stamford, A.W.,Nargund, R.,Miller, M.W. (deposition date: 2016-12-08, release date: 2017-03-15, Last modification date: 2023-10-04)

Primary citation

Scott, J.D.,DeMong, D.E.,Greshock, T.J.,Basu, K.,Dai, X.,Harris, J.,Hruza, A.,Li, S.W.,Lin, S.I.,Liu, H.,Macala, M.K.,Hu, Z.,Mei, H.,Zhang, H.,Walsh, P.,Poirier, M.,Shi, Z.C.,Xiao, L.,Agnihotri, G.,Baptista, M.A.,Columbus, J.,Fell, M.J.,Hyde, L.A.,Kuvelkar, R.,Lin, Y.,Mirescu, C.,Morrow, J.A.,Yin, Z.,Zhang, X.,Zhou, X.,Chang, R.K.,Embrey, M.W.,Sanders, J.M.,Tiscia, H.E.,Drolet, R.E.,Kern, J.T.,Sur, S.M.,Renger, J.J.,Bilodeau, M.T.,Kennedy, M.E.,Parker, E.M.,Stamford, A.W.,Nargund, R.,McCauley, J.A.,Miller, M.W.
Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.
J. Med. Chem., 60:2983-2992, 2017

PubMed Abstract: Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

PubMed: 28245354
DOI: 10.1021/acs.jmedchem.7b00045

Experimental method

X-RAY DIFFRACTION (1.69 Å)