Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy

Abstract

Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

“…Interestingly, we observed a broad reduction of gene enriched in lysosomal pathways. This is consistent with recent implications of lysosomal dysfunction in genetic and sporadic forms of FTLD-Tau ( Polito et al, 2014 ; Caballero et al, 2018 ; Silva et al, 2019 ; Xu et al, 2019 ; Silva et al, 2020 ; Xu et al, 2021a ; Bowles et al, 2021 ; Xu et al, 2021b ; Caballero et al, 2021 ; Mahali et al, 2022 ; Silva et al, 2022 ). These gene signatures were largely specific for tauopathy; however, we identified a number of lysosomal genes that were altered in iPSC-neurons from MAPT mutations and in brains from GRN mutation carriers.…”

Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality

“…To improve upon this proof-of-concept system, we next sought to generate PhosTACs that directly bind tau rather than via a fused Halotag domain. To this end, we replaced the HaloTag7 chloroalkane warhead with one based on a positron emission tomography (PET) tau tracer, which has proven to be a valuable clinical tool to specifically detect pathological tau in patients, and as a ligand for tau-targeting PROTACs . PI-2620 (Figure S1) is a newly reported derivative of the T807 PET probe that has been shown to possess higher affinity and selectivity for 4R and 3R/4R tau isoforms .…”

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

“…These compounds are composed of an E3 ligase-recruiting element, such as IMiDs that recruit CRBN, and a binding motif for the target of interest. Bifunctional degraders function in the same manner as IMiDs, by facilitating the formation of ubiquitination-competent ternary complexes [ 65 , 66 ].…”