Hing Z A, Fung H Y J, Ranganathan P, Mitchell S, El-Gamal D, Woyach J A, Williams K, Goettl V M, Smith J, Yu X, Meng X, Sun Q, Cagatay T, Lehman A M, Lucas D M, Baloglu E, Shacham S, Kauffman M G, Byrd J C, Chook Y M, Garzon R, Lapalombella R
Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA.
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Leukemia. 2016 Dec;30(12):2364-2372. doi: 10.1038/leu.2016.136. Epub 2016 May 20.
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
核输出受体Exportin 1（XPO1）介导包括肿瘤抑制因子在内的生长调节蛋白的转运，在许多癌症中过度活跃，包括慢性淋巴细胞白血病（CLL）、急性髓细胞白血病（AML）和侵袭性淋巴瘤。最近发现了一种口服核输出选择性抑制剂（SINE）化合物，可阻断XPO1功能，有望成为许多肿瘤的一种新治疗模式。其中一种化合物KPT-330（塞利尼索）在I/II期临床试验中取得了进展，但全身毒性限制其给药频率为每周两次且需要支持治疗。我们设计了一种新一代SINE化合物KPT-8602，其XPO1抑制机制和效力与之相似，但耐受性有显著改善。在包括CLL和AML在内的血液系统恶性肿瘤的临床前动物模型中评估了KPT-8602的疗效。与KPT-330相比，KPT-8602在体外显示出相似的效力，但中枢神经系统渗透性较低，这导致其耐受性增强，即使每日给药也是如此，并且与KPT-330相比，在CLL和AML小鼠模型中的生存期有所改善。KPT-8602是一种有前景的化合物，可用于血液系统恶性肿瘤和其他可见XPO1上调的癌症的进一步开发。KPT-8602更宽的治疗窗口也可能允许提高靶点疗效，从而与其他靶向抗癌疗法形成更有效的联合治疗方案。
