NVS-MLLT-1

NVS-MLLT-1 was developed against the epigenetic target YEATS containing domain of MLLT1 (also called ENL, LTG19 or YEATS1) and MLLT3 (also called AF9 or YEATS3). NVS-MLLT-1 is a potent and selective inhibitor of MLLT1/3–histone interactions. A structurally close analogue is available NVS-MLLT-C as negative control. NVS-MLLT-1 and NVS-MLLT-C are both soluble in DMSO up to 50 mM. Both probes NVS-MLLT-1 and NVS-MLLT-C show excellent selectivity over other YEATS domains (YEATS2 and YEATS4), across all bromodomains and on the kinases tested (Eurofins kinase safety panel).  NVS-MLLT-1 showed some activity on ACES (250 nM) and H3 (290nM) binding in the Eurofins principal panel (see SGC website). Of note, NVS-MLLT-1is structurally closely related to the orthogonal probe SGC-iMLLT (different heterobicycle moiety instead of isoquinoline ring) but has a different chemotype relative to orthogonal probe PFI-6. NVS-MLLT-1 has not been profiled in vivo.

CPP2278 (NVS-MLLT-1) paired with its control compound NVS-MLLT-C can be used as a cellular probe against various human cell lines carrying both wild-type ENL/AF9 and ENL p.117_118insNHL and p.111_113NPP> K variants. Given its dual targeting against the Yeats domains of ENL/AF9 and no ENL or AP9-specific chemical probe is available, caution should be taken to conclude that results obtained by NVS-MLLT-1 is due to the inhibitor of ENL or AF9 alone or their combination. To avoid unexpected off-target effects beyond the examined panels of Bromodomain proteins and kinases, NVS-MLLT-1 can also be combined with SGC-iMLLT and PFI-6 for commonly shared biological outcomes. This chemical probe is an excellent addition for the Yeats family.