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

15-前列腺素脱氢酶化学抑制剂增强造血干细胞移植

• 批准号: 9324688
• 负责人: STANTON L. GERSON
• 金额: $ 52.07万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324688
• 关键词: Adverse effects; Alpha Cell; Binding; Biological; Biological Assay; Biology; Blood; Blood Cell Count; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; CSF3 gene; Cells; Chemicals; Colon; Complex; Computer Simulation; Data; Diarrhea; Dinoprostone; Doctor of Philosophy; Dose; Drug Targeting; Dysmyelopoietic Syndromes; Elements; Engraftment; Enterocolitis; Enzymes; Erythrocytes; Fluorouracil; Generations; Goals; Half-Life; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Homing; Hospitalization; Human; In Vitro; Infection; Injury; Intestinal Mucosa; Lead; Leukocytes; Malabsorption Syndromes; Measures; Melphalan; Modeling; Morbidity - disease rate; Multiple Myeloma; Mus; Oxidoreductase; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Platelet Count measurement; Pre-Clinical Model; Predisposition; Preparation; Proliferating; Property; Prostaglandins; Protocols documentation; Publications; Radiation; Recovery; Red Blood Cell Count; Regimen; Reporting; Rodent Model; Safety; Schedule; Science; Signal Transduction; Solubility; Speed; Technology; Testing; Tissues; Transplantation Conditioning; Ulcer; White Blood Cell Count procedure; Whole-Body Irradiation; X-Ray Crystallography; analog; aqueous; base; chemotherapy; compare effectiveness; conditioning; curative treatments; design; effective therapy; gastrointestinal; gut microbiota; healing; high risk; human morbidity; improved; in vivo; inhibitor/antagonist; leukemia/lymphoma; lipophilicity; mortality; neutrophil; new therapeutic target; novel; oncology; peripheral blood; prevent; receptor; reconstitution; small molecule; small molecule inhibitor; standard of care; three dimensional structure; tissue regeneration; tool; treatment duration

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.

项目总结/摘要 我们的目标是开发探针化合物，以验证15-前列腺素脱氢酶（15-PGDH）作为一种新型药物 加速造血干细胞移植（HST）恢复的靶点。HST，包括骨 骨髓移植（BMT）是血液恶性肿瘤包括白血病的治愈性治疗， 淋巴瘤、骨髓增生异常和多发性骨髓瘤。然而，从HST恢复是缓慢的，需要延长 住院由于白色血细胞计数低，出血， 由于血小板计数低而导致的贫血，以及由于红细胞计数低而导致的贫血。我们的广泛目标 是开发15-PGDH的小分子抑制剂，以测试这些抑制剂将提高 组织中的前列腺素E2在体内的水平，从而加速恢复白色血细胞，红细胞 HST后的血小板。此外，我们试图验证15-PGDH作为治疗的新靶点， 化疗引起的胃肠小肠结肠炎，HST预处理的严重副作用。重要的是没有 目前存在用于药物诱导的小肠结肠炎或用于加速HST后恢复的治疗方法。 在最近发表在《科学》杂志上的一篇文章中，我们描述了15-PGDH的第一个体内活性抑制剂。这种酶 将PGE 2代谢成其生物学上无活性的形式15-酮-PGE 2。小分子SW 033291抑制15- PGDH，Ki<1 nM。在体内，SW 033291使骨髓和结肠中的PGE 2水平加倍。通过这个 SW 033291可加速小鼠骨髓移植后的造血恢复。它加速了 中性粒细胞、血小板和红细胞在6天内恢复。此外，SW 033291保护结肠， 用DSS或化疗剂5-FU处理的小鼠的肠粘膜。通过加快 骨髓恢复和预防小肠结肠炎，15-PGDH的抑制剂有希望显著降低i） 感染和出血并发症，和ii）其相关的死亡率和发病率在人类造血干细胞 干细胞移植 目标1侧重于药物化学。SW 033291具有低水溶性、高亲脂性， 和能够产生活性代谢物的功能。第二代抑制剂显著改善了 极性和溶解度曲线，但显示出短的体内半衰期和适度的hERG信号。在目标2和 3，我们将确认我们的抑制剂与15-PGDH结合，并将优化治疗持续时间以促进恢复 和阻止小肠结肠炎。我们还将比较抑制15-PGDH与 目前的标准治疗G-CSF，我们已经证明了至少有累加效应。我们 将另外比较15-PGDH抑制与竞争技术的有效性。最后在 目标4我们将在严格的临床前模型中测试我们优化的抑制剂的有效性和安全性。总的来说，我们 目标是1）验证加速造血干细胞移植恢复的新目标，以及2） 提供安全、有效和选择性的15-PGDH抑制剂作为经验证的先导药物。