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Haematologica. 2018 Jun;103(6):1054-1064. doi: 10.3324/haematol.2017.178376. Epub 2018 Feb 22.

A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support.

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Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Department of Pathology, Ulsan University College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA


Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation 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 prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. 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 prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.

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