A New Seonlytic - PZ?

    Navitoclax (aka ABT-263) is an experimental orally active anti-cancer drug, with some unpleasant side effects (it produces nausea and diarrhea, kills blood platlets, and has other off-target negative effects).  But recently it has been found to also be a powerful senolytic.

    Our presently available senolytics are a limited set that seem to primarily target one specific cell type: Dasatinib clears senescent adipocytes (fat cells), Fisetin clears senescent endothelial cells (blood-vessel lining), and Azithromycin clears senescent fibroblasts (skin & structure cells).  On the other hand, Navitoclax seems to be much less selective in persuading senescent cells to go into aptosis.  It acts by binding to the anti-aptotic mitochondrial transmembrane molecule Bcl-xl, degrading Bcl-xl and initiating apoptosis.  The problem is that Navitoclax lacks selectivity, which means that it often does the same job on some normal cells, particularly blood platlets.

     The senescent-cell marker enzyme β-galactosidase is present almost exclusively in senescent cells.  It acts to selectively catalyze the sugar galactose.  At present, β-galactosidase provides us with the very best way of identifying senescent cells in a thin slice of tissue sample.  One uses a dye that selectively stains β-galactosidase a dark  blue, and then counts the population fraction of blue cells, as seen in a microscope.

    An article in the April-24-2020 issue of Nature Communications has suggested a way of taming Navitoclax by hitching it to β-galactosidase.  They have made a PROTAC, a proteolysis targeting chimera, by converting Navitoclax into PZ15227, or what they call PZ for short.  The trick is to form a new molecule that joins the Bcl-xl-binding region of Navitoclax with the sugar galactose.  The joining renders the Bcl-xl-binding activity inactive unless the galactose part of the molecule is removed by β-galactosidase.  When β-galactosidase is present, it steals the galactose, freeing the remainder of the molecule to bind to Bcl-xl and to produce apoptosis.

    The research group has injected aging mice with PZ and observed  that it indeed has very powerful senolytic effects and also has reduced (but not zero) destruction of platlets.  Thus PZ has the potential of producing a safe senolytic agent that can clear the full spectrum of senescent cell types.  The paper,  however, emphasizes that while PZ is promising, it still has problems with off-target toxicity and with efficient delivery.  It is clear that we will not have the option of taking PZ as a human senolytic any time soon.