Development of Gilteritinib-Based Chimeric Small Molecules that Potently Induce Degradation of FLT3-ITD Protein
Development of Gilteritinib-Based Chimeric Small Molecules that Potently Induce Degradation of FLT3-ITD Protein
复制标题
开发基于 Gilteritinib 的嵌合小分子，可有效诱导 FLT3-ITD 蛋白降解
DOI：
10.1021/acsmedchemlett.2c00402
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发表时间：
2022
影响因子：
4.2
通讯作者：
Naito Mikihiko
中科院分区：
文献类型：
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作者：
Ohoka Nobumichi;Suzuki Masanori;Uchida Takuya;Tsuji Genichiro;Tsukumo Yoshinori;Yoshida Masayuki;Inoue Takao;Demizu Yosuke;Ohki Hitoshi;Naito Mikihiko
编码 FMS 样酪氨酸激酶 3 (FLT3) (FLT3-ITD) 的基因中的内部串联重复 (ITD) 是急性髓系白血病 (AML) 中最常见的突变。目前批准的FLT3激酶抑制剂具有较高的疗效，但临床上经常观察到FLT3激酶活性重新激活引起的耐药性。在本研究中，我们通过将 FDA 批准的 FLT3 抑制剂 gilteritinib 引入靶向蛋白质降解技术中，开发了新型 FLT3 降解剂。最活跃的化合物 CRBN(FLT3)-8 通过泛素-蛋白酶体系统有效降解 FLT3-ITD，并比 gilteritinib 更有效地抑制 FLT3-ITD 突变型 AML 细胞的增殖。这些发现为针对 FLT3-ITD 阳性癌症的降解药物提供了一种新的先导化合物。
Internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3) (FLT3-ITD) is the most frequently observed mutation in acute myeloid leukemia (AML). Currently approved FLT3 kinase inhibitors have high efficacy, but drug resistance caused by reactivation of FLT3 kinase activity is often clinically observed. In this study, we developed novel FLT3 degraders by introducing gilteritinib, an FDA-approved FLT3 inhibitor, into targeted protein degradation technology. The most active compound, CRBN(FLT3)-8, potently degraded FLT3-ITD via the ubiquitin-proteasome system and inhibited the proliferation of FLT3-ITD mutant AML cells more effectively than gilteritinib. These findings provide a new lead compound for degradation-based drugs targeting FLT3-ITD-positive cancers.