Menin is a putative tumor suppressor associated with multiple endocrine tumor type 1 (MEN-1 syndrome). Specifically, Menin has two functional nuclear localization signals and inhibits JunD transcriptional activation. MLL1, a histone methyltransferase, is an active global regulator of gene transcription. Besides, the protein belongs to histone-modifying enzyme and contains the transactivated domain 9aaTAD and participates in the epigenetic maintenance of transcriptional memory. Moreover, the protein-protein interaction targeting menin MLL is a new therapeutic strategy for acute leukemia carrying MLL fusion (MLL leukemia). The interaction between menin MLL protein and protein is essential for the expression of HOXA and Meis1 genes, which will promote the leukemia of MLL leukemia. Furthermore, the interaction between the targeted menin MLL protein and non-peptide small molecule inhibitors can achieve this goal. M-808 is a highly potent and efficacious covalent Menin-MLL interaction inhibitor.
M-808 is a highly potent and efficacious covalent Menin-MLL interaction inhibitor.
How does M-808 work on the target? Let’s study it together. In the beginning, M-808 is a highly potent and efficacious covalent Menin-MLL interaction inhibitor with a binding IC50 value of 2.6 nM. Meanwhile, M808 exhibits IC50 values of 1 nM, 4 nM and 2.8 nM in MV4;11 cells, MOLM-13 cells and HL60 cells, respectively.
In the second place, M808 forms a covalent bond between its acrylamide and the sulfur atom of Cys329 in menin. Nonetheless, M-808 (16) is well tolerated in SCID mice with intravenous administration of 10 mg/kg or 25 mg/kg every other day dosing (three times a week) for one week.
Last but not the least, M-808 achieves a maximum tumor growth inhibition (TGI) of 97% during treatment (day 35). Particularly, M-808 reduces the average tumor volume from 92 mm3 at the beginning of the treatment to 59 mm3 at day 35, with no significant toxicity.
All in all, M-808 is a highly potent and efficacious covalent Menin-MLL interaction inhibitor.
References:
Shilin Xu, et al. J Med Chem. 2020 May 14;63(9):4997-5010.