Haematologica 2018 02 22() pii 10.3324/haematol.2017.178376
Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplant and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow PGE2, and accelerates hematopoietic recovery following murine transplant. Here we describe efficacy of (+)- SW209415, a second generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 provides 10,000-fold increased solubility, affording the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo PGE2, and accelerating hematopoietic regeneration following transplant. In additional models, (+)-SW209415: i) demonstrates synergy with G-CSF, the current standard of care; ii) maintains efficacy as transplant cell dose is escalated; iii) maintains efficacy when transplant donors and recipients are aged; and iv) potentiates homing in xenotransplants using human HSC. (+)-SW209415 shows no adverse effects, showing no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high dose administration, showing no toxicity as assessed by weight, blood counts and serum chemistries. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing PGE2., and thereby advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.