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.

项目摘要/摘要我们旨在开发探针化合物，以验证15-局丁氏蛋白脱氢酶（15-PGDH）作为一种新型药物从造血干细胞移植（HST）加速恢复的靶标。 HST，包括骨头骨髓移植（BMT）是血液恶性肿瘤的治疗方法，包括白血病，淋巴瘤，骨髓增生和多发性骨髓瘤。但是，从HST恢复很慢，需要扩展住院。患者处于低白细胞计数导致感染的高风险，出血低血小板计数引起的，并且是由于低红细胞计数而引起的。我们的广泛目标是开发15-PGDH的小分子抑制剂，以检验这些抑制剂将升高的假设前列腺素E2的组织水平在体内，从而加速了白细胞，红细胞的恢复和HST之后的血小板。此外，我们试图验证15-PGDH作为治疗的新目标化学疗法诱导胃肠道小肠结肠炎，这是HST调节的严重副作用。重要的是，不目前存在针对药物诱导的小肠结肠炎或HST加速恢复的治疗方法。在最近的科学文章中，我们描述了15-PGDH的第一个体内活性抑制剂。这种酶将PGE2代谢为其生物非活性形式，15-酮PGE2。小分子SW033291抑制15- PGDH，带有Ki <1 nm。在体内，SW033291在骨髓和结肠中加倍PGE2水平。通过这个效果，SW033291在小鼠中骨髓移植后加速了造血恢复。它加快了中性粒细胞，血小板和红细胞的返回6天。此外，SW033291保护了结肠和用DSS或化学治疗5-FU治疗的小鼠的肠粘膜。通过超速骨髓恢复和预防小肠结肠炎，15-PGDH的抑制剂有望显着减少I）感染和出血并发症，以及ii）它们在人造血的相关死亡率和发病率干细胞移植。 AIM 1专注于药物化学。 SW033291患有低水溶性，高亲脂性，和可能产生反应代谢物的功能。第二代抑制剂大大改善极性和溶解度轮廓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参与15-PGDH，并将优化治疗时间以促进恢复血细胞和堵塞小肠结肠炎。我们还将比较抑制15-PGDH与当前的护理G-CSF标准，我们已经至少证明了添加剂效应。我们还将比较15-PGDH抑制经文的有效性。最后，在目标4我们将在严格的疗效和安全性临床前模型中测试我们的优化抑制剂。从广义上讲，我们的目标是1）验证从造血干细胞移植中加速恢复的新目标，以及2）提供15-PGDH的安全，有效和选择性抑制剂作为经过验证的药物铅。