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）增加了患有恶性和非恶性血液病的儿童和成人的存活率。移植前，患者接受细胞毒性药物（如环磷酰胺/白消安）和/或全身照射的预处理方案，以抑制免疫系统，并在恶性肿瘤的情况下，根除残留的癌细胞。不幸的是，调理药物和辐射对造血系统或癌细胞不是特异性的，但也会损害正常组织（例如肝、肺和肾、口腔粘膜炎），这表明开发特异性靶向造血细胞（正常和恶性）的调理剂可能具有临床益处。使用基于细胞的读出系统，我们已经确定了一种小分子（SM 27），它选择性地杀死造血来源的细胞，包括一组人白血病细胞系，正常人血细胞和小鼠骨髓细胞。我们的初步筛选提供了原则性证据，证明造血系统的特异性靶向是可行的。然而，SM 27的最大活性是在5 M浓度下，并且分子结构不稳定（例如含有酯键）。因此，该提议的目标是1）使用合成化学来修饰可能导致不稳定性的分子部分以在结构上优化SM 27，2）通过筛选新的化学文库来鉴定另外的造血特异性试剂（250，000+化合物）和3）表征针对造血和非造血细胞的广泛的人类癌细胞系的命中。本发明的目的是鉴定已知被标准调节方案靶向或损伤的造血来源细胞以及正常人组织细胞（肺、肾、肝、口腔、骨髓），以鉴定高度造血特异性的潜在先导化合物。该项目的意义在于其潜在的发展毒性较小的预处理方案HSCT治疗血液系统疾病。该提案的结果对所有需要HSCT治疗恶性和非恶性血液病的患者具有重大意义。 公共卫生相关性：造血干细胞移植（HSCT）提高了恶性和非恶性血液病高危和复发患者的生存率。然而，用于准备患者进行HSCT的预处理方案并不特异于造血来源的细胞，因此可能对肝、肺、肾和其他组织造成损伤，导致可能致命的短期和长期并发症。造血特异性调节剂的开发应该为当前方案提供毒性较小的替代方案，因此，对接受HSCT治疗血液病的患者具有重要意义。

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.