Lin Wenwei, Slavish P Jake, Phillips Aaron H, Trotter Marlon, Yang Guangwei, Chai Sergio C, Churion Kelly, Ochoada Jason, Das Sourav, Shelat Anang A, Mullighan Charles G, Kriwacki Richard W, Rankovic Zoran, Chen Taosheng
†Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, and §Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
ACS Med Chem Lett. 2025 May 5;16(6):1080-1088. doi: 10.1021/acsmedchemlett.5c00116. eCollection 2025 Jun 12.
NUP98-KDM5A oncogenic fusion protein contains the N-terminal FG-repeat domain of NUP98 and the C-terminal PHD3 finger of KDM5A. Pediatric acute myeloid leukemia patients with NUP98-KDM5A have poor prognosis and high incidence of relapse and urgently need novel therapeutics. We developed a TR-FRET assay to detect the interaction between the PHD3 domain and a H3K4-(Me3) peptide and screened a library comprising over 600,000 compounds, leading to the identification of KDM5A-PHD3 domain ligands with novel scaffolds, such as CBL-0137, UNBS5162, BIX-01294, and 3-phenyl-toxoflavin, which were subsequently confirmed via SPR and/or NMR assays. These ligands hold significant promise for therapeutic interventions in pediatric acute myeloid leukemia driven by NUP98-KDM5A, pending further development.
NUP98-KDM5A致癌融合蛋白包含NUP98的N端FG重复结构域和KDM5A的C端PHD3结构域。患有NUP98-KDM5A的小儿急性髓性白血病患者预后较差，复发率高，迫切需要新的治疗方法。我们开发了一种时间分辨荧光共振能量转移（TR-FRET）检测方法来检测PHD3结构域与H3K4-（三甲基化）肽之间的相互作用，并筛选了一个包含60多万种化合物的文库，从而鉴定出具有新型骨架的KDM5A-PHD3结构域配体，如CBL-0137、UNBS5162、BIX-01294和3-苯基毒黄素，随后通过表面等离子体共振（SPR）和/或核磁共振（NMR）检测进行了确认。这些配体在进一步开发之前，对由NUP98-KDM5A驱动的小儿急性髓性白血病的治疗干预具有重大前景。
