PH-002

PH-002 is an apolipoprotein E4 (ApoE4) structure corrector that binds to the ApoE4 amino-terminal domain and inhibits the interaction between the amino- and carboxy-terminal domains (IC₅₀ = 116 nM).^1,2 It restores intracellular trafficking of EGFP-ApoE4 through the endoplasmic reticulum and Golgi apparatus in Neuro2a cells, producing a more ApoE3-like trafficking phenotype.² PH-002 (100 nM) reduces ApoE4 fragmentation, amyloid-β (1-40) (Aβ40) and Aβ42 levels, and phosphorylated tau levels and increases GABAergic neuron numbers and GAD67 levels in neurons derived from ApoE4/E4-expressing human induced pluripotent stem cells (hiPSCs).³ It also increases transgelin 3 (TAGLN3) levels and reduces NF-κB p50 and p52 levels and pro-inflammatory cytokine production in ApoE4/E4 knock-in hiPSC-derived astrocytes stimulated with a pro-inflammatory cocktail.⁴

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1. Chen, H.-K., Liu, Z., Meyer-Franke, A., et al. Small molecule structure correctors abolish detrimental effects of apolipoprotein E₄ in cultured neurons. The Journal of Biological Chemisty 287(8), 5253-5266 (2012).

2. Brodbeck, J., McGuire, J., Liu, Z., et al. Structure-dependent impairment of intracellular apolipoprotein E₄ trafficking and its detrimental effects are rescued by small-molecule structure correctors. The Journal of Biological Chemisty 286(19), 17217-17226 (2011).

3. Wang, C., Najm, R., Xu, Q., et al. Gain of toxic apolipoprotein E₄ effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24(5), 647-657 (2018).

4. Arnaud, L., Benech, P., Greetham, L., et al. APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation. Cell Rep. 40(7), 111200 (2022).