1ysn: Difference between revisions

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.

[[Category: Armstrong, R C.]]

[[Category: Augeri, D J.]]

[[Category: Belli, B A.]]

[[Category: Connor, J M.O.]]

[[Category: Deckwerth, T L.]]

[[Category: Elmore, S W.]]

[[Category: Fesik, S W.]]

[[Category: Hajduk, P J.]]

[[Category: Joseph, M K.]]

[[Category: Korsmeyer, S J.]]

[[Category: Kunzer, A R.]]

[[Category: Mitten, M J.]]

[[Category: Nettesheim, D G.]]

[[Category: Nimmer, P M.]]

[[Category: Petros, A M.]]

[[Category: Reed, J C.]]

[[Category: Rosenberg, S H.]]

[[Category: Shoemaker, A R.]]

[[Category: Tahir, S K.]]

[[Category: Thompson, C B.]]

[[Category: Tomaselli, K J.]]

[[Category: Wendt, M D.]]

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