SGC-PI5P4Kg/MYLK-1

SGC-PI5P4Kg/MYLK-1 : Inhibitor of PIP4K2C, MYLK4

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(0 ratings)

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Probe SGC-PI5P4Kg/MYLK-1 is in the process of SERP review.

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Information

PIP4K2C
MYLK4

Inhibitor

up to 1 uM
Reviewer recommended concentration: 500 nM

Additional Data

SGC Chemical Probe Collection

In Vitro Validations

Uniprot ID: Q8TBX8

Target Class: Kinase

Target SubClass: Lipid kinase

Potency: Kd

Potency Value: 19 nM

Potency Assay: DiscoverX scanMAX assay

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Phosphatidylinositol 5-phosphate 4-kinase type-2 g ...

DOI Reference: 10.1016/j.crchbi.2022.100036

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): SGC-PI5P4Kγ/MYLK4-1 was profiled in the DiscoverX scanMAX assay against 403 wild-type kinases at 1 μM. Only 7 kinases showed PoC <10 giving an S10(1 μM) = 0.017. When the PoC <35 fraction was examined, 10 kinases were included (S35(1 μM) = 0.025). Potential off-targets within the S35(1 μM) fraction were tested via biochemical enzymatic or binding assays and/or NanoBRET target engagement assays. Off targets: PIKfyve IC50 = 12 nM, CLK2 IC50 = 370 nM; DYRK1A IC50 = 520 nM

Potency assay, off target (cells): NanoBRET analysis of cellular binding affinity for PIKfyve (NB IC50 = 450 nM), CLK2 (NB IC50 = 3200 nM), and DYRK1A (NB IC50 > 10000 nM) as off-targets is > 30-fold of that for PI5P4Kγ (NB IC50 = 67 nM), suggesting the chemical probe has enhanced selectivity when used in cells.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

Good in vitro probe. It is important to use the negative control probe in parallel as it allows to account for the off target activity on PYKfyve. The cellular engagement IC50 of 67nM was obtained in the absence of serum according to the information provided. As a result, higher probe concentrations may be required to see cellular activity if serum is present (concurrent testing of the inactive probe analogue will be especially important in this case). The conclusion section of the original manuscript (Current Research in Chemical Biology 3 (2023) 100036) provides some additional probe suggestions to further validate cellular activity is being driven by PI5P4Kγ rather than some other off target. No compound optimization for in vivo dosing was conducted and no ADME or in vivo PK data are available as of the date of this review (06/2023). Accordingly, this probe cannot be recommended for in vivo dosing.

(last updated: 12 Jun 2023 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

This probe was thoroughly characterized. Target engagement was demonstrated by different orthogonal assays. A commercial kinase panel was used to investigate selectivity. A negative-control is available. Further data on permeability, solubility and non-kinase selectivity profiles would be appreciated, although cellular activity was proven.

(last updated: 17 Jun 2024 )