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双重 FLT3/TOPK 抑制剂对 FLT3-ITD 继发突变具有活性，能够强烈抑制急性髓系白血病细胞系。

Dual FLT3/TOPK inhibitor with activity against FLT3-ITD secondary mutations potently inhibits acute myeloid leukemia cell lines.

机构信息

Purdue Institute for Drug Discovery, Department of Chemistry, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

Department of Chemistry, Purdue University, West Lafayette IN 47907, USA.

出版信息

Future Med Chem. 2018 Apr 1;10(7):823-835. doi: 10.4155/fmc-2017-0298. Epub 2018 Feb 13.

DOI:10.4155/fmc-2017-0298
PMID:29437468
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6367750/
Abstract

AIM

Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691.

RESULTS

HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines. HSD1169 was active against MV4-11 and Molm-14 (FLT3-ITD cell lines) but not NOMO-1 or HL60 (FLT3-WT cell lines). HSD1169 was also active against sorafenib-resistant Molm13-res cell line (containing FLT3-ITD/D835Y).

CONCLUSION

HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD.

摘要

目的

约 30%的急性髓系白血病（AML）患者存在 FLT3 酪氨酸激酶结构域（TKD）突变或内部串联重复（FLT3-ITD）。目前，针对耐药性 FLT3-ITD（包含 TKD 中的次要突变，主要在残基 D835/F691 处）的化合物非常少。

结果

HSD1169 是一种新型化合物，对 FLT3-ITD（D835 或 F691）具有活性。HSD1169 还对 T-LAK 细胞起源的蛋白激酶（TOPK）具有活性，TOPK 是一种在 AML 细胞系中高度表达的合作激酶。HSD1169 对 MV4-11 和 Molm-14（FLT3-ITD 细胞系）有效，但对 NOMO-1 或 HL60（FLT3-WT 细胞系）无效。HSD1169 对含有 FLT3-ITD/D835Y 的索拉非尼耐药 Molm13-res 细胞系也有效。

结论

HSD1169 或其类似物可能成为治疗含有耐药性 FLT3-ITD 的 AML 的治疗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/c510239dbf71/fmc-10-823-g7a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/e3eec20677ba/fmc-10-823-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/1ca49fd16bbd/fmc-10-823-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/1f1f8180e278/fmc-10-823-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/342e6bea62c9/fmc-10-823-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/c7601e49ca88/fmc-10-823-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/d29c3f2c6f7f/fmc-10-823-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/c510239dbf71/fmc-10-823-g7a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/e3eec20677ba/fmc-10-823-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/1ca49fd16bbd/fmc-10-823-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/1f1f8180e278/fmc-10-823-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/342e6bea62c9/fmc-10-823-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/c7601e49ca88/fmc-10-823-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/d29c3f2c6f7f/fmc-10-823-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f75/6367750/c510239dbf71/fmc-10-823-g7a.jpg

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