Targeting a Leukemia-Relevant Protein-Protein Interface: N-Aryl Anthranilic Acids as Disruptors of the c-Myb-CBP/p300 KIX Interaction.

Authors

Haifa E Alfassam, Emadeldin M Kamel, Sarah I Othman, Hanan M Alharbi, Hassan A Rudayni, Ahmed A Allam, Al Mokhtar Lamsabhi

Published in

Chemical biology & drug design. Volume 108. Issue 4. Pages e70415.

Abstract

The interaction between c-Myb and the CBP/p300 KIX domain is a key transcriptional event in acute myeloid leukemia (AML) and represents an attractive target for small-molecule intervention. In this study, we applied an integrated computational-experimental strategy to identify new N-aryl anthranilic acid disruptors of the c-Myb-KIX protein-protein interaction. A scaffold-focused library of 3656 N-aryl anthranilic acid derivatives was filtered, docked to the c-Myb-binding groove of KIX (PDB 2AGH), and the top hits were further evaluated by MD simulations, MM/PBSA, FEL, and ADMET analyses. This workflow prioritized four hits (C1-C4) for experimental testing. Computational analyses showed that all four compounds remained bound within the α1/α3 Myb-facing groove, but differed markedly in their predicted effects on the c-Myb-KIX interface. Among them, C3 emerged as the strongest predicted disruptor, whereas C1 was predicted to stabilize the complex. The $\mathrm{\Delta \Delta }{G}_{\mathrm{PPI}}$ analysis further showed that C3 produced the largest destabilizing effect on the c-Myb-KIX interface (+4.57 kcal/mol), followed by C2 (+2.30 kcal/mol) and C4 (+1.40 kcal/mol), whereas C1 stabilized the complex (-6.47 kcal/mol). These predictions were validated by microscale thermophoresis (MST). The binary c-Myb-KIX interaction showed an apparent K_d of 26.71 ± 0.54 μM, and the compounds inhibited complex formation with IC₅₀ values of 99.6 ± 20.5 μM (C1), 54.7 ± 22.1 μM (C2), 16.5 ± 0.8 μM (C3), and 27.2 ± 2.7 μM (C4). Notably, C3 outperformed the reference inhibitor Naphthol AS-E phosphate (28.8 ± 3.1 μM). Overall, these findings identify C3 as a promising lead and establish N-aryl anthranilic acids as a tractable scaffold for targeting the c-Myb-CBP/p300 KIX interaction.

PMID:
42844726
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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