Menin
December 2025
The FDA recently approved ziftomenib, an oral menin-targeting inhibitor by Kura Oncology, which marks a significant milestone for some of the most difficult-to-treat acute leukemias (relapsed or refractory NPM1ᵃ-mutated disease).
Just a year earlier, revumenib became the first menin inhibitor approved for another subtype of leukemia (KMT2Aᵇ-rearranged leukemia). These back-to-back approvals highlight menin’s emerging role in cancer treatment and offer novel options in settings with historically poor outcomes.
In this article, we highlight Menin’s journey from a little-known chromatin adaptor to a key target in precision oncology. Its intriguing protein story revolves around a hidden pocket on the protein’s surface, with structural insights playing a leading role in turning menin into a druggable target. We used 3decision’s new Storyboard feature to enhance visual representation and understanding of structural insights in a dynamic way.
The Menin Paradox: From Tumor Suppressor to Cancer Enabler
Menin is a nuclear scaffold protein encoded by the MEN1 gene that lacks any enzymatic activity. It exerts its effects through interactions with different partners, and its function highly varies depending on the specific tissue and context in which the protein is expressed.
This raises a paradox, as in the cancer context, menin can function either as a tumor suppressor or a tumor promoter.
In endocrine tissues, it acts as a tumor suppressor, and loss-of-function mutations cause the development of endocrine tumors. On the other hand, in blood-forming cells, menin flips its role and becomes a tumor promoter, partnering with other proteins such as KMT2A to drive oncogenic expression that keeps blood cells locked in an immature, cancerous state.
This mechanism opens a therapeutic window where menin inhibition can selectively target leukemia while sparing normal tissues.
Breaking the "Undruggable" Barrier: The Structural Keys to Menin Inhibition
Targeting menin was challenging because, in hematopoietic cells, it binds its partner KMT2A through two separate motifs across an extended interface – an interaction long considered “undruggable”.
The breakthrough came with high-resolution 3D structures of menin, which provided a rational foundation for overcoming this limit:
Crystal structures of menin–KMT2A: these structures (e.g., PDB: 4GQ6) uncovered a well-defined, deep pocket on menin that can accommodate a short portion of KMT2A, creating an opportunity for the design of small-molecule inhibitors.
Structures of menin–inhibitor: Publicly available structures reveal a common mechanism of action, with the ligand occupying the KMT2A pocket, thus disrupting the menin-KMT2A interaction. For instance, in the menin-revumenib complex (PDB: 7UJ4), key binding features include hydrogen bonds (Y276, W341, E366, M322) and pi-cation interactions (Y319, Y323). Compounds that preserve a similar interaction pattern, while adding extensive hydrophobic contacts within the surrounding pocket, achieve nanomolar potency.
For rapid understanding and a highly visual representation, we illustrate each step of the Menin story - from pocket discovery to inhibitor binding - using the 3decision Storyboard feature in the video below.
Menin’s Emerging Resistance: A Structural Rationale
Despite the success of menin inhibitors, recent studies have reported relapse in some patients after treatment with revumenib. This has been attributed to mutations in menin at key residues (M322, G326, T344) within the inhibitor binding site.
Structural analysis of the menin mutant M322I in complex with the drug revumenib (PDB: 8E90) revealed:
Mutation hotspots: The mutated residues (M322, G326, T344) cluster around W346 but do not overlap with the binding interface of KMT2A.
Steric clash effect: In the M322I mutant, the branching methyl group of I322 protrudes toward the ligand, creating a steric clash and thus disrupting the hydrogen bonds with W341 side chain and M322 backbone. The inhibitor affinity is thus significantly reduced while leaving other interactions intact.
The result of these mutations is that menin and KMT2A remain bound on chromatin, sustaining oncogenic signaling despite therapy. To overcome resistance, second-generation inhibitors are currently under development, leveraging these structural insights to design ligands capable of maintaining high affinity even in the presence of mutations.
We present the resistance mechanism as a new chapter in the Storyboard, extending the initial story into a complete structural narrative.
Conclusion
Menin inhibitors not only offer new hope for patients facing some of the most aggressive forms of leukemia, but they also demonstrate how structural biology drives innovation in drug discovery — whether it’s overcoming resistance or designing better drugs.
Abbreviations
ᵃNPM1 = nucleophosmin 1
ᵇKMT2A = Histone-lysine N-methyltransferase 2A
Curious about the new 3decision Storyboard feature?
This interactive session allows you to visualize each step in the protein journey as a connected and interactive narrative and share it seamlessly with your team for collaborative discussions and presentations.
Storyboard feature is a central part of the 3decision 2.2 release. Explore how it works in the video below:
Reference:
Perner, Florian et al. “MEN1 mutations mediate clinical resistance to menin inhibition.” Nature vol. 615,7954 (2023): 913-919. doi:10.1038/s41586-023-05755-9