Chemical Inhibitors of 15-prostaglandin dehydrogenase Potentiate Hematopoietic Stem Cell Transplantation

点击翻译按钮获取中文摘要

Project Summary/Abstract We aim to develop probe compounds to validate 15-prostaglandin dehydrogenase (15-PGDH) as a novel drug target for accelerating recovery from hematopoietic stem cell transplantation (HST). HST, including bone marrow transplantation (BMT) is a curative treatment for hematological malignancies including leukemias, lymphomas, myelodysplasias, and multiple myeloma. However, recovery from HST is slow, requiring extended hospitalization. Patients are at high risk of infections resulting from low white blood cell counts, bleeding resulting from low platelet count, and are anemic, resulting from low red blood cell counts. Our broad objective is to develop small molecule inhibitors of 15-PGDH to test the hypothesis that these inhibitors will elevate tissue levels of prostaglandin E2 in vivo, and thereby accelerate recovery of white blood cells, red blood cells and platelets following HST. Moreover, we seek to validate 15-PGDH as a novel target for the treatment chemotherapy induced gastrointestinal enterocolitis, a severe side effect of HST conditioning. Importantly, no current treatments exist for drug-induced enterocolitis or for accelerating recovery following HST. In a recent article in Science, we described the first in vivo active inhibitor of 15-PGDH. This enzyme metabolizes PGE2 to its biologically inactive form, 15-keto-PGE2. The small molecule SW033291 inhibits 15- PGDH with Ki<1 nM. In vivo, SW033291 doubles PGE2 levels in the bone marrow and colon. Through this effect, SW033291 accelerates hematopoietic recovery after bone marrow transplantation in mice. It speeds the return of neutrophils, platelets and erythrocytes by 6 days. Moreover, SW033291 protected the colon and intestinal mucosa of mice that had been treated with either DSS or the chemotherapeutic 5-FU. By speeding bone marrow recovery and preventing enterocolitis, inhibitors of 15-PGDH have promise to markedly reduce i) infection and bleeding complications, and ii) their associated mortality and morbidity in human hematopoietic stem cell transplantation. Aim 1 focuses on medicinal chemistry. SW033291 suffers from low aqueous solubility, high lipophilicity, and functionality that could generate reactive metabolites. A second generation inhibitor substantially improves the polarity and solubility profile, but displays a short in vivo half-life and a modest hERG signal. In Aims 2 and 3, we will confirm that our inhibitors engage 15-PGDH and will optimize treatment duration to promote recovery of blood cells and block enterocolitis. We will also compare the effectiveness of inhibition of 15-PGDH versus the current standard of care G-CSF, for which we have already demonstrated at least an additive effect. We will additionally compare the effectiveness of 15-PGDH inhibition verses a competing technology. Finally, in aim 4 we will test our optimized inhibitors in rigorous preclinical models of efficacy and safety. Broadly, our goals are to 1) validate a new target for accelerating recovery from hematopoietic stem cell transplant, and 2) provide safe, potent and selective inhibitors of 15-PGDH as validated drug leads.