SBIR TOPIC 255

急性髓性白血病（AML）是一种起源于骨髓的侵袭性造血系统癌症。AML是成人白血病中最常见的形式;老年人目前的最佳治疗反应率为6-8%。长期目标是将MRxl 02的开发推进到AML的临床治疗，这是一种未满足的医疗需求。MRx 102是天然产物雷公藤内酯醇的创新衍生物，其通过抑制关键的细胞内信号传导途径对AML原始细胞和细胞系具有细胞毒性。雷公藤甲素诱导40%急性白血病完全缓解的中国临床研究初步大鼠毒理学结果表明MRxl 02可能具有改善的毒性特征。在这些提出的研究中，将在裸鼠人AML异种移植模型中评估MRxl 02剂量反应关系，并用两种另外的AML细胞系扩展。将通过比较血浆生物利用度来确定MRxl 02的最佳给药途径，并将评价备用化合物的活性。根据初步结果和申请人对其他雷公藤内酯醇衍生物的经验，预计MRx 102在AML异种移植模型中表现出优异的疗效和良好的效力，足以在II期合同中进行进一步的临床前开发，从而进行IND使能药理学和GLP毒理学研究、IND备案和临床评价。

Acute Myeloid Leukemia (AML) is an aggressive hematopoietic cancer originating in the bone marrow. AML is the most common form of adult leukemia; older adults have a 6-8% best current therapy response rate. The long-term objective is advancing the development of MRxl02 to clinical treatment of AML, an unmet medical need. MRx102 is an innovative derivative of the natural product triptolide, which is cytotoxic for AML blasts and cell lines by inhibiting critical intracellular signaling pathways. Triptolide induced 40% complete acute leukemia responses in a Chinese clinical study. Preliminary rat toxicology results suggest MRxl02 may have an improved toxicity profile. In these proposed studies, the MRxl02 dose response relationship will be assessed in the nude mouse human AML xenograft model, and extended with two additional AML cell lines. The optimal route of administration for MRxl02 will be determined by comparison of plasma bioavailability, and backup compounds will be evaluated for activity. Based on preliminary results and applicant experience with other triptolide derivatives, MRx102 is expected to show excellent efficacy with good potency in the AML xenograft models sufficient to enable further preclinical development in the Phase II contract leading to IND-enabling pharmacology and GLP toxicology studies, IND filing and clinical evaluation.