INHIBITORS OF THE PHD ZINC FINGER TO TREAT ANEMIA

PROJECT SUMMARY ABSTRACT Anemia is common disease and is associated with many conditions including end stage renal disease Recombinant versions of Erythropoeitin EPO the key hormone that regulates red blood cell mass have been a mainstay of treatment for this condition The necessity of parenteral administration however has prompted the search for alternative methods for increasing red cell mass In this regard a subset of patients with erythrocytosis harbor loss of function mutations in the Prolyl Hydroxylase Domain protein PHD also known as EGLN gene thereby identifying the encoding protein PHD as an attractive target to increase red cell mass PHD is the key enzyme that downregulates Hypoxia Inducible Factor HIF which in turn activates the EPO gene Indeed there are efforts underway elsewhere to inhibit the active site of PHD as an approach to treating anemia However the catalytic domain of PHD is homologous to other proteins thereby warranting efforts to more specifically inhibit PHD PHD is distinctive in harboring a zinc finger domain that like its catalytic domain is essential for efficient downregulation of HIF In the present application we propose targeting this zinc finger in order to increase HIF and thereby increase red cell mass In preliminary studies we have conducted an Alpha Screen for compounds that can inhibit the interaction between the zinc finger of PHD and its ligand which serves to recruit PHD to the HSP pathway to facilitate HIF hydroxylation We have identified compounds that can disrupt this interaction We propose the following Specific Aims First we wish to identify structure activity relationships with the aim of improving inhibition Second we seek to attain acceptable ADME PK drug values for at least one or two compounds Third we propose injecting this compound s into a novel knockin mouse line in which the Phd gene has a humanized zinc finger so as to allow interaction with compounds identified by the in vitro studies Accordingly this application involves a partnership that brings together the medicinal chemistry expertise of the Fox Chase Chemical Diversity Center with the experience of the Principal Investigator s laboratory at the University of Pennsylvania in examining the HIF pathway The long term goal of this project will be to identify a preclinical candidate that can be evaluated in more detailed IND directed studies Such a candidate will be promising agent for the treatment of anemia NARRATIVE The oxygen sensor PHD regulates the hormone Erythropoeitin and therefore red cell mass We propose inhibiting the activity of a key domain of PHD namely its zinc finger with small molecules Such compounds will have utility in the treatment of anemia which is characterized by low red cell mass