Cindy Sobotka-Briner

Publications (2)3.83 Total impact

• Article: Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis.

  Clay W Scott, Cindy Sobotka-Briner, Deidre E Wilkins, Robert T Jacobs, James J Folmer, William J Frazee, Ratan V Bhat, Smita V Ghanekar, David Aharony
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  ABSTRACT: Caspase-3 is an intracellular cysteine protease, activated as part of the apoptotic response to cell injury. Its interest as a therapeutic target has led many to pursue the development of inhibitors. To date, only one series of nonpeptidic inhibitors have been described, and these have limited selectivity within the caspase family. Here we report the properties of a series of anilinoquinazolines (AQZs) as potent small molecule inhibitors of caspase-3. The AQZs inhibit human caspase-3 with Ki values in the 90 to 800 nM range. A subset of AQZs are equipotent against caspase-6, although most lack activity against this isoform and caspase-1, -2, -7, and -8. The AQZs inhibit endogenous caspase-3 activity toward a cell permeable, exogenously added substrate in staurosporine-treated SH-SY5Y cells. The AQZs reduce biochemical and cellular features of apoptosis that are thought to be a consequence of caspase-3 activation including DNA fragmentation, TUNEL staining, and the various morphological features that define the terminal stages of apoptotic cell death. Moreover, the AQZs also inhibit apoptosis induced by nerve growth factor withdrawal from differentiated PC12 cells. Thus, the AQZs represent a new and structurally novel class of inhibitors, some of which selectively inhibit caspase-3 and will thereby allow evaluation of the role of caspase-3 activity in various cellular models of apoptosis.
  Journal of Pharmacology and Experimental Therapeutics 02/2003; 304(1):433-40. · 3.83 Impact Factor
• Article: MOLECULAR CLONING OF THE GUINEA-PIG IL-5 RECEPTOR α AND β SUBUNITS AND RECONSTITUTION OF A HIGH AFFINITY RECEPTOR

  Clay W Scott, Naomi J. Logsdon, Deidre E. Wilkins, Tyrrell E. Norris, Cindy Sobotka-Briner, Stephen Hubbs, Alexander Graham
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  ABSTRACT: The functional IL-5 receptor is a heteromeric complex consisting of an α and β subunit. The cloning, sequencing and expression of guinea-pig IL-5Rα and β subunits is described. The guinea-pig IL-5Rα subunit cDNA encodes a protein of Mr47 kDa, which is 72 and 66% homologous to the human and murine orthologs, respectively. Three guinea-pig IL-5Rβ subunit cDNA clones were isolated, which differ in the N-terminus and are 56–64% homologous to the human and murine IL-5Rβ subunits. Expressing human IL-5Rαβ and guinea-pig IL-5Rαβ1in the baculovirus-insect cell system resulted in recombinant receptors which bound hIL-5 with high affinity (Kd=0.19 and 0.11 nM, respectively). Expressing just gpIL-5Rα was not sufficient to demonstrate binding. This contrasts with the human receptor, where hIL-5Rα alone can bind hIL-5 with high affinity. gpIL-5Rαβ1bound both hIL-5 and mIL-5 with comparable affinity (Ki=0.10 and 0.06 nM), similar to that seen with hIL-5Rαβ. Thus, both the heteromeric hIL-5R and gpIL-5Rαβ1can bind multiple IL-5 orthologs with high affinity whereas the murine IL-5R is selective for the murine ligand.
  Cytokine.