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1.
Scheme 1

Scheme 1. From: Brain Penetrant LRRK2 Inhibitor.

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.
2.
Figure 1

Figure 1. From: Brain Penetrant LRRK2 Inhibitor.

LRRK2 inhibitors. (a) Biochemical inhibition of GST-LRRK2 (1326–2527), GST-LRRK2[G2019S] (1326–2527), GST-LRRKT[A2016T] (1326–2527), and GST-LRRK2[G2019S + A2016T] (1326–2527) was assayed using 20 μM Nictide in the presence of 100 μM ATP. Results are averages of triplicate experiments.

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.
3.
Figure 5

Figure 5. From: Brain Penetrant LRRK2 Inhibitor.

Pharmacodynamic analysis for HG-10-102-01 (4). Pharmacodynamic study of HG-10-102-01 (4) from brain, spleen, and kidney following intraperitoneal administration at the indicated doses. Tissues were collected, and endogenous LRRK2 was resolved by SDS-PAGE and blotted with a phospho-specific antibody directed against Ser910, Ser935, and total LRRK2 (the quantitative analysis is included in the Supporting Information).

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.
4.
Figure 2

Figure 2. From: Brain Penetrant LRRK2 Inhibitor.

Molecular model of HG-10-102-01 (4) with LRRK2[T2016]. (a) Two hydrogen bonds are predicted between the hinge region A1950 and the aminopyrimidine motif of the inhibitor. One hydrogen bond is predicted between the backbone amide carbonyl of S1954 with the amide carbonyl of the inhibitor. (b) Two potential interactions exist between M1947 and T2016 with the 5-chloro group on the pyrimidine of the inhibitor.

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.
5.
Figure 3

Figure 3. From: Brain Penetrant LRRK2 Inhibitor.

Compound HG-10-102-01 (4) inhibits LRRK2 in cells. HEK293 cells stably expressing (a) wild-type GFP-LRRK2, (b) GFP-LRRK2[G2019S], (c) GFP-LRRK2[A2016T], and (d) GFP-LRRK2[G2019S + A2016T] were treated with DMSO or increasing concentrations of 4 for 90 min (1 μM of LRRK2-IN-1 was used as a control). Cell lysates were subjected to immunoblotting for detection of LRRK2 phosphorylated at Ser910 and Ser935 and for total LRRK2.

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.
6.
Figure 4

Figure 4. From: Brain Penetrant LRRK2 Inhibitor.

Compound 4 inhibits endogenously expressed LRRK2. (a) Endogenous LRRK2 from EBV immortalized human lymphoblastoid cells from a control subject (LRRK2+/+), a PD patient homozygous for the LRRK2[G2019S] mutation. After treatment of the cells with DMSO or the indicated concentration of 4 [or LRRK2-IN-1 (1)] for 90 min, cell lysates were subjected to immunoblot analysis with the indicated antibody for western analysis. Immunoblots were performed in duplicate, and the results were representative of at least two independent experiments. (b) As in a, except mouse Swiss 3T3 cells were used. (c) As in a, except mouse embryonic fibroblast cells were used.

Hwan Geun Choi, et al. ACS Med Chem Lett. 2012 August 9;3(8):658-662.

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