SMG1i

SMG1i : Inhibitor of SMG1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

SMG1

Inhibitor

0.3-1.0 uM

Probe Availability:

In Vitro Validations

Uniprot ID: Q96Q15

Target Class: Kinase

Target SubClass: PI3/PI4

Potency: IC50

Potency Value: 0.11 nM

Potency Assay: Biochemical assay

PDB ID for probe-target interaction (3D structure): 7PW7

Target aliases:

Serine/threonine-protein kinase SMG1, LIP, KIAA042 ...

DOI Reference: 10.1016/j.bmcl.2012.08.107

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): tested in 25 additional kinases and was found to have IC50 >10 μM across the panel, with the exceptions of GSK α and β (α = 260 nM and β = 330 nM). PI3K was not part of the standard panel but the α and γ isoforms were measured separately for several compounds, which showed consistently weaker inhibition of PI3K than mTOR

Probe Selectivity in Vitro:

IC50s mTOR 50 nM, CDK1 32000 mM, CDK2 7100 nM, PI3Ka 92 nM, PI3Kg 60 nM

Potency assay, off target (cells): In MDA 361 cells it shows little effect on phospho p70s6 K and phospho AKT, targets of mTOR and PI3K.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

The hSMG-1 inhibitor disclosed by Pfizer in the 2012 BMCL publication appears to be a tool compound of reasonable quality. Two concerns remain that need to be taken into account when using this compound. The depression of selectivity which is often seen in cells with kinase inhibitors, has also been demonstrated in this paper. While compound 11j clearly shows a level of cellular selectivity, it remains unclear how selective it is since the authors do not provide a full d.r. evaluation and a cellular IC50 is not disclosed. A preferred use of 300 nM in a cellular experiment not to exceed 1 uM seems advisable to avoid confounding data. The 2nd concern is the lack of kinome data for the proposed chemical probe; the compound was only studied in a small panel of '25 additional kinases' which is a mere 5% of the kinome. While data is available for closely related kinases that the compound was optimized against, this is not a guarantee there are no other off-targets to be aware of. A good control compound is not available, since selectivity data for less potent compounds is missing, in particular wrt CDK1/2.

(last updated: 6 Nov 2022 )

SERP Ratings

In Cell Rating

SERP Comments:

This molecule is a very selective hSMG-1 inhibitor with cellular activity and hence a useful probe.

(last updated: 6 Nov 2022 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

The compound was only tested against 25 kinases and no in cellulo target engagement assay was performed. The compound needs further profiling. Based on the aminopyrimidine scaffold it is likely to be a promiscuous kinase inhibitor.

(last updated: 22 Mar 2023 )