SGC-iMLLT

SGC-iMLLT was developed based on a low micromolar MLLT1 YEATS domain inhibitor which was identified in a medium throughput screening campaign using AlphaScreen technology. Docking studies utilizing an available crystal structure of MLLT1:H3Kac27 peptide (PDB ID 5J9S) guided the design approach and medicinal chemistry efforts to yield SGC-iMLLT including extensive SAR studies (>200 derivatives). SGC-iMLLT is a selective inhibitor of the YD of MLLT-1 and -3 with no observed off-target activity against related acyllysine reading domains (10 µM compound concentration, AlphaScreen) and 48 recombinant human bromodomain proteins (50 µM compound concentration, thermal shift assay). The binding mode of SGC-iMLLT to MLLT1 YD was deciphered using X-ray crystallography (PDB ID 6HT1) confirming its interaction with the Kac/Kcr binding site of MLLT1 YD. Target engagement was demonstrated by CETSA (MV-4-11 cells, MLLT1) as well as FRAP (U2OS cells transfected with GFP‐tagged MLLT1 and MLLT3), and NanoBRET (HEK293 cells, MLLT3) studies. Moreover, SGC-iMLLT reduces MYC, DDN expression while it increases CD86 expression in MV-4-11 AML. Metabolic stability of SGC-iMLLT was investigated in primary human hepatocytes demonstrating moderate metabolic resistance (t_1/2 53 min). The primary metabolic process was determined to be N-demethylation. However, SGC-iMLLT was not used in in vivo studies. SGC-iMLLT is structurally similar to NVS-MLLT-1.

The compound shows potency of IC50: 300 nM in a cell free assay and should be used in cellular assays up to 1 uM. No data are available assessing its toxicity or suitability for in vivo use. No efficacy data are shown for in vivo suitability and few DMPK data are available, showing a rapid metabolism by hepatocytes with a half-life of 53 min. Caveat: Desmotropie (stable benzimidazole isomers), i.e. compound can be drawn in different versions.