Browsing by Subject "small molecule inhibitors"

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    Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections
    (Elsevier, 2019-07-01) Washburn, Alex; Abdeen, Sanofar; Ovechkina, Yulia; Ray, Anne-Marie; Stevens, Mckayla; Chitre, Siddhi; Sivinski, Jared; Park, Yangshin; Johnson, James; Hoang; Hoang, Quyen Q.; Chapman, Eli; Parish, Tanya; Johnson, Steven M.; Biochemistry and Molecular Biology, School of Medicine
    Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria.
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    Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin
    (American Association for Cancer Research, 2019-06-01) Sima, Livia Elena; Yakubov, Bakhtiyor; Zhang, Sheng; Condello, Salvatore; Grigorescu, Arabela A.; Nwani, Nkechiyere G.; Chen, Lan; Schiltz, Gary E.; Arvanitis, Constandina; Zhang, Zhong-Yin; Matei, Daniela; Medicine, School of Medicine
    Tissue transglutaminase (TG2) is a multi-functional protein, with enzymatic, GTP-ase and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High throughput screening identified several small molecule inhibitors (SMIs) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second generation analogues (MT1–6). ELISA demonstrated that these analogues blocked TG2/FN interaction and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase (FAK). Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal (ip) dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer (OC) cells to the peritoneum. Pre-treatment with MT4 also sensitized OC cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche.