Trinity College of Arts & Sciences, Duke University, Durham, North Carolina.
Department of Neurosurgery, Duke University, Durham, North Carolina.
Mol Cancer Ther. 2020 Sep;19(9):1763-1769. doi: 10.1158/1535-7163.MCT-20-0069. Epub 2020 Jun 30.
Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.
近年来，酪氨酸激酶抑制剂在癌症治疗领域掀起了一场革命，极大地提高了慢性髓性白血病（CML）及其他疾病患者的生存率。然而，这些抑制剂的脱靶毒性是众所周知的，耐药性已成为一个首要关注的问题。新型的艾伯斯坦（ABL）家族酪氨酸激酶的别构抑制剂，包括 GNF-2、GNF-5 和 ABL-001，有能力克服这些问题。多项当代研究表明，它们在三个关键领域具有潜在的疗效：原发性血液系统和实体恶性肿瘤、转移以及与其他小分子药物的联合应用。此外，正在进行的临床试验正在研究 ABL-001 治疗 CML 和复发性实体肿瘤的疗效。这项工作回顾了 GNF-2 和 GNF-5 的临床前测试以及 ABL-001 的临床前和临床测试的现有文献。未来的研究将继续评估这些有前途的抑制剂，作为实体肿瘤的一线治疗药物，并在更传统的药物如伊马替尼失效时作为挽救治疗药物。
