Optimization of small molecule integrin activators to enhance cord blood transplant

项目总结 本提案是对Catalyst：产品的资助机会公告RFA-HL-20-027的回应 小分子和生物制品的定义.初步产品/铅系列鉴定(R33.临床试验 不允许)授予机制。造血干细胞移植已成为首选治疗方法 治疗血液系统恶性肿瘤和某些遗传性疾病。脐带血已经成为一种诱人的 替代骨髓或外周血作为移植的造血干细胞来源。由于一项 不那么严格的人类白细胞抗原配型要求，脐带血移植使患者能够得到相反的治疗 找不到合适的捐赠者。不幸的是，这些制剂中的干细胞较少，这导致 免疫重建延迟率。这可能会导致机会性感染的发生率更高。 这增加了移植物失败率和移植相关死亡率。找到一种方法来提高生产率 脐血移植的免疫重建将转化为更好的结果和更广泛的结果 对成人患者的适用性。提高脐带血细胞植入率的努力包括针对 细胞粘附级联调节细胞归巢、外渗和滞留在骨髓中。这一过程 是通过趋化因子以及细胞黏附的选择素和整合素家族来协调的。 分子。通过体外治疗细胞来改善细胞的功能已经产生了令人振奋的结果 选择素和趋化因子介导的过程。这些预处理步骤的缺点是它们需要 额外的时间、专业知识和费用。到目前为止，由于缺乏合适的整合素，整合素还没有被靶向 试剂。我们已经开发出一种小分子家族，可以激活脐带血细胞上的整合素， 促进它们与骨髓中的反受体相互作用。我们已经证明了- 使用家族中有代表性的成员的概念，在人类移植后给这种化合物配药 CD34+脐血细胞进入NOD-SCID小鼠导致CD34+细胞在骨髓中植入增加 外周血中CD45+细胞计数增加。这些化合物可以独立于细胞给药。 而且大规模合成的成本通常不高。这将比其他方法更有优势 不需要对细胞进行预处理或操作的技术将意味着更负担得起的 和普遍可翻译的疗法。尽管前景看好，但我们的先导化合物存在口服生物利用度低的问题。 部分原因是它被CYP3A4代谢。这些问题降低了脐带血移植的吸引力。 由于潜在的药物-药物相互作用以及可能需要的多天给药方案 临床前动物模型。这份R33拨款提案包括旨在解决CYP3A4的结构性警报 生成新一代化合物的活性，具有降低代谢负担和改善口腔功能的特点 药物动力学。如果成功，这将导致确定要进展到的临床候选对象 研究性新药(IND)-使研究成为可能。

PROJECT SUMMARY This proposal is in response to the funding opportunity announcement RFA-HL-20-027 for the Catalyze: Product Definition for Small Molecules and Biologics - Preliminary Product/Lead Series Identification (R33 - Clinical Trial Not Allowed) granting mechanism. Hematopoietic stem cell transplantation has become a preferred treatment for hematological malignancies and certain genetic disorders. Umbilical cord blood has become an appealing alternative to bone marrow or peripheral blood as a source of hematopoietic stem cells for transplant. Due to a less stringent HLA match requirement, cord blood transplant has allowed patients to be treated that otherwise could not find a suitable donor. Unfortunately, there are fewer stem cells in these preparations which results in delayed rates of immunological reconstitution. This can lead to a higher incidence of opportunistic infections which increases the rate of graft failures and transplant related mortalities. Finding a means to improve the rate of immune reconstitution with cord blood transplants would translate to improved outcomes as well as broader applicability to adult patients. Efforts to improve the rate of engraftment of cord blood cells include targeting the cell adhesion cascade which mediates cell homing, extravasation and retention in the bone marrow. This process is coordinated through the function of chemokines as well as the selectin and integrin families of cell adhesion molecules. Promising results have been generated by treating the cells ex-vivo to improve the function of the selectin- and chemokine-mediated processes. A drawback to these preconditioning steps is they require additional time, expertise and expense. As yet the integrins have not been targeted due to a lack of suitable reagents. We have developed a family of small molecules that can activate integrins on cord blood cells, facilitating their interaction with their counter-receptors in the bone marrow. We have demonstrated proof-of- concept using a representative member of the family that dosing such a compound following transplant of human CD34+ cord blood cells into NOD-SCID mice leads to increased engraftment of CD34+ cells in the bone marrow and increased CD45+ cell counts in peripheral blood. These compounds can be dosed independently of the cells and are typically inexpensive to synthesize on a large-scale. This would have an advantage over other technologies as no preconditioning or manipulations of the cells would be required meaning a more affordable and universally translatable therapy. Although promising, our lead compound suffers from low oral bioavailability in part due to it being metabolized by CYP3A4. These issues make it less attractive for cord blood transplant due to potential drug-drug interactions as well as the multi-day dosing regimen that will likely be required based on preclinical animal models. This R33 grant proposal includes aims to address the structural alerts for CYP3A4 activity to generate a next generation compound with decreased metabolic liabilities and improved oral pharmacokinetics. If successful, this should result in identifying a clinical candidate to progress into Investigational New Drug (IND)-enabling studies.