GW788388

Inhibitor of TGFBR1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(1 ratings)

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Probe GW788388 is in the process of SERP review.

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Information

TGFBR1

Inhibitor

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Probe Availability:

In Vitro Validations

Uniprot ID: P36897

Target Class: Protein kinase

Target SubClass: TKL

Potency: IC50

Potency Value: 18 nM

Potency Assay: ALK5 Fluorescence Polarization Binding Assay with intracellular kinase domain from ALK5.

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

Structure-activity relationship: Yes, see J Med Chem paper

Target aliases:

TGF-beta receptor type-1, TGFBR1, TGFR1_HUMAN, Tbe ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 p38alpha: 7.2 uM

Potency assay (off target): In an in vitro panel of kinases, GW788388 only inhibited p38a >50% at 10 uM (panel included: P70S6K, AMPK, CHK1, CSK, JNK1, LCK, MKK1, MSK1, MAPK2, PDK1, PhosK, PKA, PKC A, SGK, p38 alpha, p38 beta).

Probe Selectivity in Vitro:

In an in vitro panel of kinases, GW788388 only inhibited p38a >50% (IC50 of 7.28 µM) at 10 uM (panel included: P70S6K, AMPK, CHK1, CSK, JNK1, LCK, MKK1, MSK1, MAPK2, PDK1, PhosK, PKA, PKC A, SGK, p38 alpha, p38 beta). In U2OS cells, GW788388 had no effect on BMP-induced Smad1/5 phosphorylation. Radiometric assay of ALK (caALK)5, TβRII, BMPRII, transfected cells with subsequent IP of the kinase showed activity on TGFBR1, ACVR1B, ACVR1C, TGFBR2; cellular selectivity showed inhibition of ALK4, ALK5 and ALK7 activity.

Potency assay, off target (cells): In U2OS cells, GW788388 had no effect on BMP-induced Smad1/5 phosphorylation.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

The data for the probe was recorded some time ago. Today, kinase selectivity panels would typically be more comprehensive. Further selectivity testing should be considered.

(last updated: 26 Aug 2021 )

SERP Ratings

In Cell Rating

SERP Comments:

The probe validation is a bit meagre and based on one assay from 2006. The assay, a fluorescence polarization displacement assay using rhodamine labelled ATP, is known to have a large variability (much like seen in the original paper) and proven to inflate binding affinities. For a probe to be declared such, I would imagine at the least two more robust and orthogonal validating assays, and perhaps an X-ray structure. Because the rest of the data depends on these considerations, I refrain from commenting on the cellular and in vivo data for now. I wonder if the authors since 2006 have acquired additional binding or inhibition data that confirm the FP assay data reported here.

(last updated: 21 Sept 2021 )