Novel Hematopoietic Conditioning Agents for Treatment of Hematological Diseases

描述(由申请人提供)：造血干细胞移植(HSCT)提高了患有恶性和非恶性血液疾病的儿童和成人的存活率。在移植前，患者接受细胞毒性药物(如环磷酰胺/丁硫丹)和/或全身照射的调节方案，以抑制免疫系统，如果是恶性肿瘤，则根除残留的癌细胞。不幸的是，调理药物和辐射并不是针对造血系统或癌细胞的，还会损害正常组织(如肝、肺、肾、口腔粘膜炎)，这表明开发专门针对造血细胞(正常和恶性)的调理剂可能会有临床益处。使用基于细胞的读出系统，我们已经识别出一种小分子(SM27)，它选择性地杀死来自造血细胞的细胞，包括一组人类白血病细胞系、正常人类血细胞和小鼠骨髓细胞。我们的初步筛查提供了原则证据，证明了针对造血系统的特异性靶向是可行的。然而，SM27的最大活性是在5M浓度下，并且该分子是结构不稳定的(例如，含有酯键)。因此，这项建议的目标是1)使用合成化学方法对SM27进行结构优化，以修饰可能导致不稳定的分子部分；2)通过筛选新的化学库(250,000+化合物)来确定更多的造血特异性药物；以及3)鉴定针对广泛的造血和非造血来源的人类癌细胞系以及标准条件下已知的靶向或损伤的正常人体组织细胞(肺、肾、肝、口腔、骨髓)的命中结果，以便确定潜在的具有高度造血特异性的先导化合物。这个项目的意义在于它有可能开发出一种毒性较低的造血干细胞移植预适应方案，用于治疗血液病。这项建议的结果对所有需要HSCT治疗恶性和非恶性血液病的患者都有重大影响。 公共卫生相关性：造血干细胞移植(HSCT)提高了患有恶性和非恶性血液病的高危和复发患者的存活率。然而，用于为HSCT患者做准备的预适应方案并不针对造血细胞，因此可能会对肝、肺、肾和其他组织造成损害，导致可能致命的短期和长期并发症。造血特异体调剂的开发应该提供一种毒性较低的替代方案，因此，对接受造血干细胞移植治疗血液病的患者具有重大意义。

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) has increased the survival of children and adults afflicted with malignant and non-malignant hematological diseases. Prior to transplant, patients receive a conditioning regimen of cytotoxic drugs (e.g. cyclophosphamide/busulfan) and/or total body irradiation in order to suppress the immune system and, in the case of malignancies, eradicate remaining cancer cells. Unfortunately, conditioning drugs and radiation are not specific for the hematopoietic system or cancer cells but also damage normal tissues (e.g. liver, lungs and kidneys, oral mucositis), suggesting that developing conditioning agents that specifically target hematopoietic cells (normal and malignant) may have clinical benefit. Using a cell-based readout system, we have identified a small molecule (SM27) that selectively kills cells of hematopoietic origin, including a panel of human leukemia cell lines, normal human blood cells and mouse bone marrow cells. Our preliminary screening provides proof-of-principle evidence that specific targeting of the hematopoietic system is feasible. However, the maximum activity of SM27 is at 5M concentrations and the molecule is structurally unstable (e.g. contains an ester linkage). Therefore, the goals of this proposal are 1) to structurally optimize SM27 using synthetic chemistry to modify portions of the molecule that may be responsible for instability, 2) to identify additional hematopoietic-specific agents through the screening of novel chemical libraries (250,000+ compounds) and 3) to characterize hits against a wide panel of human cancer cell lines of hematopoietic and non-hematopoietic origina as well as normal human tissue cells (lung, kidney, liver, oral, bone marrow) known to be targeted or damaged by standard conditioning regimens in order to identify potential lead compounds that are highly hematopoietic-specific. The significance of this project lies in its potential for developing a less toxic conditioning regimen for HSCT for treatment of hematological diseases. The results of this proposal have major implications for all patients requiring HSCT for the treatment of malignant and non-malignant hematological diseases. PUBLIC HEALTH RELEVANCE: Hematopoietic stem cell transplantation (HSCT) has improved the survival rates of high-risk and relapsed patients suffering from malignant and non-malignant hematological diseases. However, conditioning regimens used to prepare patients for HSCT are not specific to cells of hematopoietic origin and thus can cause damage to liver, lung, kidneys and other tissues leading to short-term and long-term complications that can be potentially fatal. The development of hematopoietic-specific conditioning agents should provide a less toxic alternative to current regimens and, thus, has major implications for patients receiving HSCT for the treatment of hematological diseases.