| Structural highlights
4b05 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 1fkn, 1m4h, 1py1, 1sgz, 1tqf, 1ujj, 1ujk, 1w50, 1w51, 1xn2, 1xn3, 1xs7, 1ym2, 1ym4, 2b8l, 2b8v, 2fdp, 2va5, 2va6, 2va7, 2vie, 2vij, 2viy, 2viz, 2vj6, 2vj7, 2vj9, 2vkm, 2vnm, 2vnn, 2wez, 2wf0, 2wf1, 2wf2, 2wf3, 2wf4, 2wjo, 2xfi, 2xfj, 2xfk, 4acu, 4acx, 4azy, 4b00 |
| Activity: | Memapsin 2, with EC number 3.4.23.46 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2]
Publication Abstract from PubMed
Beta-site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (Abeta) species. Since cerebral deposition of Abeta species might be critical for the pathogenesis of Alzheimers disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical FRET assay, Abeta and sAPPbeta release from modified and wild type human SH-SY5Y cells, mouse N2A cells, as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and Cathepsin D were 14 and >1000 fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain and CSF Abeta levels in mouse, guinea pig and non-human primate. Pharmacokinetic/ Pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduce the levels of Abeta in brain, CSF and plasma in several preclinical species. It might therefore have disease-modifying potential in the treatment of Alzheimers disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.
Discovery of AZD3839, a potent and selective BACE1 clinical candidate for the treatment of Alzheimers Disease.,Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, Radesater AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Falting J J Biol Chem. 2012 Oct 9. PMID:23048024[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, Radesater AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Falting J. Discovery of AZD3839, a potent and selective BACE1 clinical candidate for the treatment of Alzheimers Disease. J Biol Chem. 2012 Oct 9. PMID:23048024 doi:http://dx.doi.org/10.1074/jbc.M112.409110
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