Browsing by Subject "Small-molecule inhibitors"

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    Impact of Optimized Ku–DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response
    (MDPI, 2024-09-26) Mendoza-Munoz, Pamela L.; Deshwar Kushwaha, Narva; Chauhan, Dineshsinha; Gacem, Karim Ben Ali; Garrett, Joy E.; Dynlacht, Joseph R.; Charbonnier, Jean-Baptiste; Gavande, Navnath S.; Turchi, John J.; Medicine, School of Medicine
    Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku-DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment.
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    Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking
    (National Academy of Sciences, 2018-11-06) Chen, Xingjuan; Liu, Degang; Zhou, Donghui; Si, Yubing; Xu, David; Stamatkin, Christopher W.; Ghozayel, Mona K.; Ripsch, Matthew S.; Obukhov, Alexander G.; White, Fletcher A.; Meroueh, Samy O.; Cellular and Integrative Physiology, School of Medicine
    Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.
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    Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
    (Elsevier, 2023) Battistello, Elena; Hixon, Kimberlee A.; Comstock, Dawn E.; Collings, Clayton K.; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S.; Hinkley, Madeline M.; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W. Nicholas; Witkowski, Matthew T.; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall; Medicine, School of Medicine
    Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.