NVS-MLLT-1

Protein target name:

MLLT1, MLLT3

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

5-10 uM

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

YEATS

HUGO ID:

HGNC:7134 HGNC:7136

Entrez gene ID:

4298 4300

UNIPROT ID:

Q03111 P42568

Target alias:

ENL; LTG19; YEATS1; AF9; YEATS3

Probe Details

Chemical Probes Portal ID:

CPP2278

SMILES string:

C[C@H]1CCCN1Cc1nc2cc(ccc2[nH]1)NC(c1ccc2cnccc2c1)=O

InChi Key:

ZRTFTZCKJUNZIU-HNNXBMFYSA-N

Control compound:

NSV-MLLT-C

Orthogonal probe:

SGC-iMLLT, PFI-6SR-0813

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50, KD

150 nM MLLT1, 254 nM MLTT3, 109 nM KD MLLT1

Potency assay:

TR-FRET, ITC

Off target activity

Probe Selectivity in Vitro:

The AlphaScreen assays were employed to screen NVS-MLLT-1 against a panel of bromodomains. NVS-MLLT-1 shows potent activity on MLLT1/3 whilst being selective for YEATS2/4. NVS-MLLT-1 shows selectivity across all bromodomains (CERC2 IC50 > 40 μM).

Outside target family: NVS-MLLT-1 shows no activity on kinases tested, NVS-MLLT-1 has some activity on ACES and E3 binding. NVS-MLLT-C (control Compound) shows no activity in a panel of kinases, and no activities on other targets tested.

In cell validation

On target activity in cells

Potency in cells:

IC50

500 nM

Potency assay (cells):

NanoBRET cellular target engagement assay

Target engagement assay (cells):

Fluorescence Recovery After Photobleaching (FRAP) assay

Primary Reference

Reference (doi):

10.1101/2021.02.08.430291

External Resources

Available data:

SGC Chemical Probes

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

Part of SGC Chemical Probe Collection

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB Comments

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.

Mar 29 2021 - 9:14pm

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.

May 4 2021 - 1:44pm

NVS-MLLT-1

Probe Information

Target Details

ENL; LTG19; YEATS1; AF9; YEATS3

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

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NVS-MLLT-1

Probe Information

Target Details

ENL; LTG19; YEATS1; AF9; YEATS3

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?