8IT9

Co-crystal structure of FTO bound to 22

Summary for 8IT9

• Entry DOI: 10.2210/pdb8it9/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-[(2,6-diethyl-4-pyridin-4-yl-phenyl)amino]-6-(1,4-oxazepan-4-ylmethyl)benzoic acid, 2-OXOGLUTARIC ACID, ... (4 entities in total)
• Functional Keywords: rna demethylase, rna binding protein, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 57066.32

Authors

Yang, C.-G.,Gan, J.H. (deposition date: 2023-03-22, release date: 2024-02-14)

Primary citation

Xiao, P.,Duan, Z.,Liu, Z.,Chen, L.,Zhang, D.,Liu, L.,Zhou, C.,Gan, J.,Dong, Z.,Yang, C.G.
Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties.
J.Med.Chem., 66:9731-9752, 2023

PubMed Abstract: The fat mass and obesity-associated protein (FTO) is an RNA -methyladenosine (mA) demethylase highly expressed in diverse cancers including acute myeloid leukemia (AML). To improve antileukemia drug-like properties, we have designed /ZLD115, a flexible alkaline side-chain-substituted benzoic acid FTO inhibitor derived from FB23. A combination of structure-activity relationship analysis and lipophilic efficiency-guided optimization demonstrates that /ZLD115 exhibits better drug-likeness than the previously reported FTO inhibitors, FB23 and /Dac85. Then, /ZLD115 shows significant antiproliferative activity in leukemic NB4 and MOLM13 cell lines. Moreover, /ZLD115 treatment noticeably increases mA abundance on the AML cell RNA, upregulates gene expression, and downregulates gene expression in MOLM13 cells, which are consistent with gene knockdown. Lastly, /ZLD115 exhibits antileukemic activity in xenograft mice without substantial side effects. This FTO inhibitor demonstrates promising properties that can be further developed for antileukemia applications.

PubMed: 37418628
DOI: 10.1021/acs.jmedchem.3c00543

Experimental method

X-RAY DIFFRACTION (2.14 Å)