Anandhan Annadurai

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• Velma, G., Laham, M., Lewandowski, C., Valencia-Olvera, A., Balu, D., Moore, A., Ackerman-Berrier, M., Rychetsky, P., Penton, C., Musku, S., Annadurai, A., Sulaiman, M., Ma, N., & J Thatcher, G. (2024). Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer’s Disease Validated in a Mouse Model Expressing Human APOE3/APOE4. Journal of Medicinal Chemistry, 67(17). doi:10.1021/acs.jmedchem.4c00733
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  Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer’s disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-β pathology.
• Ambrose, A., Sivinski, J., Zerio, C., Zhu, X., Godek, J., Kumirov, V., Coma Brujas, T., Torra Garcia, J., Annadurai, A., Schmidlin, C., Werner, A., Shi, T., Zavareh, R., Lairson, L., Zhang, D., & Chapman, E. (2023). Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78. Journal of Medicinal Chemistry, 66(1). doi:10.1021/acs.jmedchem.2c01631
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  A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms. The top compounds were all tested against a panel of cancer cell lines and disappointingly showed little effect. The top-performing compound, 8, was retested using a series of endoplasmic reticulum (ER) stress-inducing agents and found to synergize with these agents. Finally, 8 was tested in a spheroid tumor model and found to be more potent than in two-dimensional models. The optimized Grp78 inhibitors are the first reported isoform-selective small-molecule-competitive inhibitors of an Hsp70-substrate interaction.