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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要我们的目标是开发探针化合物来验证 15-前列腺素脱氢酶 (15-PGDH) 作为一种新药加速造血干细胞移植（HST）恢复的目标。 HST，包括骨骨髓移植（BMT）是一种治疗血液系统恶性肿瘤的方法，包括白血病、淋巴瘤、骨髓增生异常和多发性骨髓瘤。然而，HST 的恢复速度缓慢，需要更长的时间住院治疗。患者因白细胞计数低、出血而面临高感染风险血小板计数低导致的，红细胞计数低导致贫血。我们的广泛目标是开发 15-PGDH 的小分子抑制剂来测试这些抑制剂会升高体内前列腺素E2的组织水平，从而加速白细胞、红细胞的恢复和 HST 后的血小板。此外，我们寻求验证 15-PGDH 作为治疗的新靶点化疗引起胃肠道小肠结肠炎，是HST调理的严重副作用。重要的是，没有目前存在针对药物引起的小肠结肠炎或加速 HST 后恢复的治疗方法。在《科学》杂志最近的一篇文章中，我们描述了第一个 15-PGDH 体内活性抑制剂。这种酶将 PGE2 代谢为其无生物活性的形式 15-酮-PGE2。小分子 SW033291 抑制 15- Ki<1 nM 的 PGDH。在体内，SW033291 使骨髓和结肠中的 PGE2 水平加倍。通过这个作用，SW033291加速小鼠骨髓移植后的造血恢复。它加快了 6 天后中性粒细胞、血小板和红细胞恢复。此外，SW033291 保护结肠和已接受 DSS 或化疗药物 5-FU 治疗的小鼠肠粘膜。通过超速行驶骨髓恢复和预防小肠结肠炎，15-PGDH 抑制剂有望显着减少 i) 感染和出血并发症，以及 ii) 与人类造血系统相关的死亡率和发病率干细胞移植。目标 1 侧重于药物化学。 SW033291具有低水溶性、高亲脂性、以及可以产生反应性代谢物的功能。第二代抑制剂显着改善极性和溶解度曲线，但显示出较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康复血细胞并阻止小肠结肠炎。我们还将比较 15-PGDH 的抑制效果与当前的 G-CSF 护理标准，我们已经证明了至少具有累加效应。我们此外，还将比较 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疗效和安全性模型中测试我们优化的抑制剂。广义上讲，我们的目标是 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 抑制剂作为经过验证的先导药物。