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A Second-Generation 15-PGDH Inhibitor Promotes Bone Marrow Transplant Recovery Independently of Age, Transplant Dose and Granulocyte Colony-Stimulating Factor Support

A Second-Generation 15-PGDH Inhibitor Promotes Bone Marrow Transplant Recovery Independently of Age, Transplant Dose and Granulocyte Colony-Stimulating Factor Support

Amar Desai, Yongyou Zhang, Youngsoo Park, Dawn M Dawson, Gretchen A Larusch, Lakshmi Kasturi, David Wald, Joseph M Ready, Stanton L Gerson, Sanford D Markowitz

Haematologica. 2018 Jun;103(6):1054-1064.

PMID: 29472361

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP459147398	SW033291		459147-39-8	Price

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