Browsing by Author "Yeh, I-Ju"

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    Exploring Covalent Bond Formation at Tyr-82 for Inhibition of Ral GTPase Activation
    (Wiley, 2023) Landgraf, Alexander D.; Yeh, I-Ju; Ghozayel, Mona K.; Bum-Erdene, Khuchtumur; Gonzalez-Gutierrez, Giovanni; Meroueh, Samy O.; Biochemistry and Molecular Biology, School of Medicine
    Ral RAS GTPases are directly activated by KRAS through a trimeric complex with a guanine exchange factor. Ral is considered undruggable and lacks an accessible cysteine for covalent drug development. Previously we had reported an aryl sulfonyl fluoride fragment that formed a covalent bond at Tyr-82 on Ral and created a deep and well-defined pocket. Here, we explore this pocket further through design and synthesis of several fragment derivatives. The fragment core is modified by introducing tetrahydronaphthalene or benzodioxane rings to enhance affinity and stability of the sulfonyl fluoride reactive group. The deep pocket in the Switch II region is also explored by modifying the aromatic ring of the fragment that is ensconced into the pocket. Compounds 19 (SOF-658) and 26 (SOF-648) formed a single robust adduct specifically at Tyr-82, inhibited Ral GTPase exchange in buffer and in mammalian cells, and blocked invasion of pancreatic ductal adenocarcinoma cancer cells. Compound 19 (SOF-658) was stable in buffer, mouse, and human microsomes suggesting that further optimization could lead to small molecules to probe Ral activity in tumor models.
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    NQO1-Bioactivatable Therapeutics as Radiosensitizers for Cancer Treatment
    (IntechOpen, 2020) Singh, Naveen; Motea, Edward A.; Huang, Xiumei; Starcher, Colton L.; Silver, Jayne; Yeh, I-Ju; Pay, S. Louise; Su, Xiaolin; Russ, Kristen A.; Boothman, David A.; Bey, Erik A.; Biochemistry and Molecular Biology, School of Medicine
    Developing cancer therapeutics that radiosensitize in a tumor-selective manner remains an ideal. We developed a novel means of radiosensitization, exploiting NAD(P)H:Quinone Oxidoreductase 1 (NQO1) overexpression, and lowered catalase expression in solid human tumors using NQO1-bioactivatable drugs. Non-small cell lung (NSCLC), pancreatic (PDAC), prostate, and breast cancers overexpress NQO1. Ionizing radiation (IR) creates a spectrum of DNA lesions, including lethal DNA double-strand breaks (DSBs), and mutagenic but rarely lethal altered DNA bases and DNA single-strand breaks (SSBs). NQO1-bioactivatable drugs (e.g., β-lapachone and deoxynyboquiones) also promote abasic DNA lesions and SSBs. These hyperactivate poly (ADP-ribose) polymerase 1 (PARP1) and dramatically increase calcium release from the endoplasm reticulum (ER). Exposure of human cancer cells overexpressing NQO1 to NQO1-bioactivatable drugs immediately following IR, therefore, hyperactivates PARP1 synergistically, which in turn depletes NAD+ and ATP, inhibiting DSB repair. Ultimately, this leads to cell death. Combining IR with NQO1-bioactivatable drugs allows for a reduction in drug dose. Similarly, a lower IR dose can be used in combination with the drug, reducing the effects of IR on normal tissue. The combination treatment is effective in preclinical animal models with NSCLC, prostate, and head and neck xenografts, indicating that clinical trials are warranted.