8SON

Crystal structure of macrophage migration inhibitory factor in complex with N-[3-(Trifluoromethyl)phenyl]-3-(2-chloroanilino)-2-cyano-3-thioxopropanamide

Summary for 8SON

• Entry DOI: 10.2210/pdb8son/pdb
• Descriptor: Macrophage migration inhibitory factor, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, isomerase, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 38425.24

Authors

Pantouris, G.,Lolis, E. (deposition date: 2023-04-28, release date: 2024-05-22, Last modification date: 2025-06-04)

Primary citation

Pantouris, G.,Khurana, L.,Tilstam, P.,Benner, A.,Cho, T.Y.,Lelaidier, M.,Perree, M.,Rosenbaum, Z.,Leng, L.,Foss, F.,Bhandari, V.,Verma, A.,Bucala, R.,Lolis, E.J.
Inhibition of MIF with an Allosteric Inhibitor Triggers Cell Cycle Arrest in Acute Myeloid Leukemia.
Acs Omega, 10:17441-17452, 2025

PubMed Abstract: Macrophage migration inhibitory factor (MIF) is a key modulator of innate and adaptive immunity that has been extensively reported to promote tumor cell survival, proliferation, and metastasis. A recent study focusing on the microenvironment of acute myeloid leukemia (AML) showed that pharmacological inhibition of MIF signaling, as well as , reduces AML cell survival. Such data highlights the crucial role of MIF in AML pathogenesis and support the efforts for developing selective MIF modulators. Here, we report the identification and crystallographic characterization of a MIF inhibitor (compound ) with an allosteric binding motif. Single point screening of against a panel of National Cancer Institute (NCI) 60 human tumor cell lines revealed a selective antitumor activity for the AML cell line HL-60. After confirming the protein's expression in multiple AML cell lines, we utilized to extract mechanistic insights into MIF action. Our findings demonstrate that AML cells utilize an MIF-dependent proliferation mechanism, which upon inhibition triggers a G0/G1 cell cycle arrest of the malignant cells. Complementary analysis of the MIF receptors utilizing neutralizing antibodies and selective small molecule antagonists associates this effect with inhibition of CD74 activation. The collection of data presented herein highlights the important role of MIF in proliferation of AML cells and points to the need of developing small molecule anticancer therapeutics that target MIF signaling.

PubMed: 40352549
DOI: 10.1021/acsomega.4c10969

Experimental method

X-RAY DIFFRACTION (1.63 Å)