Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML.

Authors

Xuanmin Lian, Yue Gao, Wenjing Du, Chengcheng Xu, Xiaowu Dong, Jinxin Che, Yubo Zhou, Jia Li, Tao Liu

Published in

Journal of medicinal chemistry. Oct 03, 2025. Epub Oct 03, 2025.

Abstract

FLT3 inhibitors (FLT3i) are effective for treating acute myeloid leukemia (AML), but acquired and adaptive resistance pose significant challenges. Therefore, finding a novel AML therapy that overcomes resistance is necessary. Proteolysis-targeting chimeras (PROTACs) are a new approach in drug discovery, offering a promising strategy for targeting FLT3 mutations in the development of effective anti-AML therapies. Our previous study found that simultaneously targeting FLT3 and CHK1 can upregulate p53 level and downregulate c-Myc level, thus overcoming adaptive resistance. We combined the merits of both PROTACs and dual targeting drugs to design a series of dual FLT3/CHK1 PROTACs. The optimal compound A28 effectively degraded FLT3 and CHK1 in a proteasome-dependent manner. Also, A28 potently inhibited FLT3 signaling, downregulated c-Myc, and upregulated p53 level. Further studies indicated that A28 had the potential to overcome acquired and adaptive resistance. Importantly, weekly intravenous administration of A28 sustained tumor growth suppression in MV-4-11 subcutaneous xenograft models.

PMID:
41043047
Bibliographic data and abstract were imported from PubMed on 04 Oct 2025.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.