L3MBTL3 MBT Domain Blocker, UNC1215

A cell-permeable pyrrolidinyl-piperidinyl-benzamide that effectively competes against H4K20Me2 peptide for L3MBTL3 binding by targeting the first two L3MBTL3 MBT domains (K_d = 120 nM in binding studies using recombinant 3MBT fragment), while exhibiting much reduced potency against L3MBTL1-H4K20Me1, 53BP1-H4K20Me2, MBTD1-H4K20Me1, or L3MBTL4-H2AK36Me1 interaction (IC₅₀ ≥2 µM; [peptide] = 150 nM). Shown to increase GFP-L3MBTL fusion nucleus mobility (10 nM to 1 µM) in HEK293 transfectants. X-ray structural analysis reveals two 3MBT are bridged together by two UNC1215 molecules in a reciprocal fashion.

Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.

A cell-permeable, highly stable (no degradation in 72 h in HEK cultures), non-cytotoxic (up to 100 µM and 24 h in HEK293T/17 cultures) pyrrolidinyl-piperidinyl-benzamide compound that effectively competes against H4K20me2 peptide (aa 17-25; 150 nM) for L3MBTL3 (200 nM) binding (IC₅₀ = 40 nM) by targeting the first two L3MBTL3 MBT domains (K_d = 120 nM in binding studies using recombinant 3MBT fragment), while exhibiting much reduced potency against L3MBTL1-H4K20me, 53BP1-H4K20me2, MBTD1-H4K20me, or L3MBTL4-H2AK36me interaction (IC₅₀ = 2, 4, 11, and 16 µM, respectively; [peptide] = 150 nM). Selectivity profiling against panels of non-Kme readers likewise reveals only weak UNC1215 potency against FLT3 kinase activity (by 64% at 10 µM), M1-mediated Ca²⁺ mobilization (IC₅₀ = 3.6 µM; stimulant = 10 nM acetylcholine), or M2-mediated cAMP production (by 30% at 30 µM; stimulant = 100 nM acetylcholine). UNC1215 is shown to increase GFP-full-length L3MBTL fusion (GFP-FLMBT) nucleus mobility in a dose-dependent manner (10 nM to 1 µM; by FRAP) and fluorescent mero76-UNC1215 conjugate is demonstrated to co-localize with GFP-FLMBT in HEK293 transfectants. X-ray structural analysis using 3MBT fragment reveals two 3MBT are bridged together by two UNC1215 molecules in a reciprocal fashion, with the domain 1 and 2 Kme-binding pocket of each 3MBT being targeted by a different UNC1215 molecule and with each UNC1215 simultaneously targeting domain 1 from one 3MBT and domain 2 from the other 3MBT.

Cell permeable: yes

Primary Target
Kme binding ligand of L3MBTL3

Reversible: yes

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

James, L.I., et al. 2013. Nat. Chem. Biol.9, 184.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)