Protein Degradation Strategies to Overcome Menin Drug Resistance in Acute Leukemias

. The heterogeneous genetic and epigenetic alterations that are associated with the development of acute leukemias renders drug discovery especially challenging. Chromosomal rearrangements of the lysine methyltransferase 2A (KMT2A) gene, which was previously known as the mixed-lineage leukemia 1 (MLL1 or MLL) gene are observed in substantial subsets of adult and childhood AML and ALL cases (5-10% of adult and 80% of infant ALL cases), where they confer a dismal prognosis (5-year survival ~35%). MENIN is a crucial co-factor of oncogenic MLL-rearranged (MLLr) fusion proteins, and the protein–protein interaction (PPI) between MENIN and MLL is vital for the development and biology of these leukemias. Current therapeutics are ineffective against MLLr leukemias, highlighting this urgent unmet medical need. Disrupting this PPI represents an enticing prospect for discovering new antileukemic therapies. Excitingly, clinical trials are ongoing with MENIN inhibitors (MENINi), but patients have developed resistance rapidly, and MENINi’s are yet to receive FDA approval. Importantly, the clinically-observed point mutations responsible for this resistance are all associated with the MENIN–MLL binding interface, where all known MENINi’s bind, including MI-853. Drugs that can accomplish sustained inhibition of their biological targets are anticipated to elicit an improved therapeutic effect. Protein degraders, which typically operate catalytically, inherently overcome drug resistance that manifests through target upregulation, and this may also minimize dosing requirements. PROteolysis-TArgeting Chimeras (PROTACs) constitute one class of degraders, wherein a ligand for the protein of interest (POI) is chemically linked to an E3 ubiquitin ligase ligand, resulting in proteasomal degradation of the POI. Various PROTACs are now undergoing clinical trials. Interestingly, since they function through event-driven, rather than occupancy-driven, pharmacology, PROTACs may retain degrading activity against protein mutants that are resistant to inhibition by the ligand from which the PROTAC was built. Hydrophobic-tagged (HyT) degraders are somewhat underexplored predecessors to PROTACs, and may offer distinct advantages (i.e. lower molecular weights, often no dependency on an E3 ligase), but it is believed they must be sustained, tight binders to realize targeted protein degradation. Herein, we describe leveraging the preclinical MENIN inhibitor MI-853, whose efficacy is predicted to be limited against MENIN mutants. We propose to exploit a solvent-exposed piperazine motif of MI-853 that is also close to the surface cysteine residue Cys329, to develop (i) MENIN PROTACs, and (ii) covalent, HyT MENIN degraders through chemical reaction with Cys329. Accordingly, our two-pronged strategy will afford two classes of MENIN degraders. Crucially, we predict that their additional mechanisms of action (beyond standard non-covalent interactions) will lay the foundation for the development of therapeutics that can achieve the sustained inhibition of MENIN, and we hope to discover one such pre-clinical candidate. Project Number: 1R21CA302901-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Steven Fletcher (+1 co-PI) | Institution: UNIVERSITY OF MARYLAND BALTIMORE, BALTIMORE, MD | Award Amount: $399,829 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-V (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371874