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Increasing numbers of papers describing YEATS biology are emerging, and there is a growing need for high quality chemical probes that can be used to study YEATS domains. A collaboration between Pfizer and the SGC has resulted in the discovery of PFI-6, a potent inhibitor of MLLT1/3. PFI-6 has a unique chemotype relative to the current MLLT1/3 chemical probe NVS-MLLT-1. PFI-6N has also been developed as a structurally similar negative control compound.
Physical and chemical properties for PFI-6
No. of chiral centres
No. of rotatable bonds
No. of hydrogen bond acceptors
No. of hydrogen bond donors
Physical and chemical properties for PFI-6N
PFI-6 shows potent activity on MLLT1/3 (Table 1). PFI-6 is universally inactive in the SGC Bromodomain panel, and showed no activity in an Invitrogen panel of 40 kinases (screening conducted at 10µM). Additionally, PFI-6 showed no activity in a panel of 25 PDEs, ion channels and GPCRs >50µM. The negative control, PFI-6N, was not reactive against MLLT1 >30µM, MLLT3 >30µM, YEATS2 >30µM and YEATS4 >30µM.
HTRF IC50 (µM)
BLI Kd (µM)
Tm Shift (°C)
Table 1: Potency Against Target Family
Figure 1: PFI-6 specfically inhibits MLLT1 and MLLT3.
In the NanoBRET cellular target engagement assay, PFI-6 displayed potent inhibition, with an average IC50 value of 0.76 μM (±0.1) (Figure 1). In comparison, PFI-6N had no inhibitory properties (up to 30 μM) (Figure 1). Further in cell validation using a Fluorescence Recovery After Photobleaching (FRAP) assay was used to confirm target inhibition by PFI-6 (Figure 2) .
Figure 1: A NanoBRET assay was used to determine MLLT3 target engagement in cells.
Figure 2: Confirmation of MLLT1 target engagement in cells by Fluorescence Recovery After Photobleaching analysis.
The figure below shows PFI-6 is soaked into the YEATS domain. PDB codes will be added when they become available.