Therapy Type: Small Molecule
Target Type: APP and Amyloid-Related (timeline), Metals
Condition(s): Alzheimer's Disease, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Huntington's Disease (Phase 2)
Company: Prana Biotechnology Limited
PBT2 is a second-generation metal-protein attenuating compound (MPAC). It does not act as a metal chelator but rather as an ionophore that facilitates translocation of copper and zinc. It is thought that by facilitating the translocation of copper and zinc into the cell, PBT2 reduces extracellular levels of these metals and thereby reduces metal-mediated Aβ aggregation (Lannfelt et al., 2008; Crouch et al., 2011).
The association of metal ions (copper, zinc, and iron) with Aβ promotes its aggregation (Bush et al., 1994).
- Bush AI, Pettingell WH, Paradis MD, Tanzi RE. Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem. 1994 Apr 22;269(16):12152-8. PubMed.
- Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW, . Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. PubMed.
- Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI, Parker SJ, Greenough MA, Volitakis I, Adlard PA, Cherny RA, Masters CL, Bush AI, Barnham KJ, White AR. The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem. 2011 Oct;119(1):220-30. PubMed.
- Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev. 2014 Feb 21;2:CD005380. PubMed.