Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment

Zhuoyao Chen, Gamma Chi, Timea Balo, Xiangrong Chen, Beatriz Ralsi Montes, Steven C. Clifford, Vincenzo D’Angiolella, Timea Szabo, Arpad Kiss, Tibor Novak, András Herner, András Kotschy and Alex N. Bullock ()
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Zhuoyao Chen: University of Oxford
Gamma Chi: University of Oxford
Timea Balo: Servier Research Institute of Medicinal Chemistry
Xiangrong Chen: University of Oxford
Beatriz Ralsi Montes: University of Oxford
Steven C. Clifford: Newcastle University Centre for Cancer
Vincenzo D’Angiolella: Crewe Road South
Timea Szabo: Servier Research Institute of Medicinal Chemistry
Arpad Kiss: Servier Research Institute of Medicinal Chemistry
Tibor Novak: Servier Research Institute of Medicinal Chemistry
András Herner: Servier Research Institute of Medicinal Chemistry
András Kotschy: Servier Research Institute of Medicinal Chemistry
Alex N. Bullock: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Neomorphic mutations and drugs can elicit unanticipated effects that require mechanistic understanding to inform clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. Here, we identify that these neomorphic interactions are mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 capture 2:1 and 2:2 KBTBD4-HDAC2 complexes, as well as a 2:1:1 KBTBD4-HDAC2-CoREST1 complex, at resolutions spanning 2.7 to 3.3 Å. The mutant and drug-induced complexes adopt similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 is identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshapes the same surface of KBTBD4 providing an example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4, while structure-activity relationship (SAR) analysis of UM171 reveals analog S234984 as a more potent molecular glue for future studies.

Date: 2025
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DOI: 10.1038/s41467-025-58350-z

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