First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

GNF-7作为一种多靶点激酶抑制剂，可同时抑制ACK1与GCK双激酶，为克服NRAS突变型急性髓系白血病（Acute Myeloid Leukemia, AML）提供了全新治疗策略。本研究针对靶向NRAS突变驱动型AML的GNF-7衍生物开展构效关系（Structure-Activity Relationship, SAR）研究，成功筛选得到活性极强的抑制剂10d、10g及11i，此类化合物对ACK1与GCK均具有个位数纳摩尔级的抑制活性。此类化合物可通过诱导细胞凋亡及阻断AKT/mTOR信号通路，强效抑制NRAS突变型AML细胞的增殖。化合物11i在激酶抑制活性、细胞活性及选择性细胞毒性方面均优于GNF-7。此外，化合物10k具备优良的小鼠体内药代动力学特性，可显著延长植入Ba/F3-NRAS-G12D细胞的小鼠生存期，并能有效延缓OCI-AML3异种移植模型的肿瘤生长，且未出现GNF-7所致的明显毒性反应。综上，本研究为针对NRAS突变驱动型AML的新型ACK1与GCK双靶点激酶抑制剂的设计提供了重要理论参考。