Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.
Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.
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DOI：
10.1038/s41598-018-21839-3
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发表时间：
2018-02-27
影响因子：
4.6
通讯作者：
Li HY
中科院分区：
文献类型：
--
作者：
Bharate JB;McConnell N;Naresh G;Zhang L;Lakkaniga NR;Ding L;Shah NP;Frett B;Li HY
FMS样酪氨酸激酶3（FLT 3）是临床验证的急性髓性白血病（AML）靶点。靶向FLT 3的抑制剂已在临床研究中进行了评估，并显示出治疗FLT 3驱动的AML的潜力。一个常见的临床限制是FLT 3选择性，因为认为FLT 3和c-KIT的伴随抑制会导致剂量限制性骨髓抑制。通过合理的设计方法，采用吡啶/嘧啶弹头合成新型FLT 3抑制剂。从研究中鉴定的最有效的化合物是化合物13 a，其对FLT 3激酶的IC 50值为13.9 ± 6.5 nM，与c-KIT相比具有高选择性。作用机制研究表明，13 a是一种II型激酶抑制剂，这也得到了计算机辅助药物发现（CADD）的支持。基于细胞的测定鉴定出13 a对具有临床相关性的多种FLT 3驱动的细胞系是有效的。我们在此报告了基于4，6-二氨基嘧啶的II型FLT 3抑制剂的发现和治疗评价，其可以作为FLT 3选择性支架用于进一步的临床开发。
FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.
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