Exploiting the BH4 domain of Bcl-2 as a novel target for the development of peptidomimetics that promote pro-apoptotic Ca2+ signaling.

Intracellular Ca2+ homeostasis plays a pivotal role in the control of cell survival and cell death. Importantly, proteins known to prevent programmed cell death, like the family of anti-apopototic Bcl-2-family members, are often up-regulated in uncontrolled cell proliferation of cancer cells. In addition, these proteins directly bind to intracellular Ca2+-release channels, like inositol 1,4,5-trisphosphate receptors (IP3Rs), thereby affecting their functional properties and promoting pro-survival Ca2+ signaling. Recently, we have elucidated a novel molecular mechanism by which anti-apoptotic Bcl-2 proteins inhibit the release of Ca2+ by blocking IP3Rs. We have revealed the molecular determinants responsible for the formation of Bcl-2/channel-protein complexes. Now, we want to exploit these novel insights to develop a novel class of small molecules that specifically interfere with these Bcl-2/channel-protein complexes and promote pro-death Ca2+ signaling. We aim to design and select molecules that are able to prevent binding of Bcl-2 to the IP3R and to stimulate Ca2+ release through the IP3R. Application of these compounds in cancer cells could potentially induce cell death and improve the therapeutic window of existing anti-cancer molecules or strategies.

Keywords:Bcl-2, Small molecules, Binbding, IP3R, Cell death, Calcium, Cancer

Disciplines:Analytical chemistry, Biochemistry and metabolism, Systems biology, Medical biochemistry and metabolism, Medicinal and biomolecular chemistry, Molecular and cell biology, Plant biology, Biophysics