In tauopathies such as Alzheimer's disease, the aggregation and increased phosphorylation of tau proteins are key pathological features. These changes in tau are strongly linked to neurodegeneration, making it a prime target for therapeutic intervention. Through chemoinformatic analyses, 2-phenyloxazole (PHOX) derivatives were identified as promising polypharmacological agents that could inhibit tau aggregation and modulate its phosphorylation. PHOX15 has been shown to restore the normal interaction of tau with microtubules in neurons and inhibit the initial phase of tau aggregation in vitro. Additionally, PHOX15 has been observed to suppress the activity of significant tau kinases, namely GSK3β and Cdk5, and decrease tau phosphorylation at sites relevant to disease progression. Molecular dynamics simulations have revealed that PHOX15's binding in tau protofilaments may hinder their transformation into PHF-like conformations. Complementary mass spectrometry experiments in Rat PC12 wild-type cells treated with PHOX15 demonstrated notable alterations in the kinome upon this treatment. This project highlights the potential of PHOX15 as a valuable drug candidate to mitigate tau-induced neurodegeneration. For more details, see Pinzi L, Conze C et al. “Quantitative Live Cell Imaging of a Tauopathy Model Enables the Identification of a Polypharmacological Drug Candidate That Restores Physiological Microtubule Regulation.” BioRxiv, 2022. https://doi.org/10.1101/2022.10.31.514565.