TX1-85-1
Covalent Inhibitor of ERBB3
Structure
In Cells
In Model Organisms
SERP ratings and comments
SERP Ratings
(last updated: 12 Jun 2016 )
SERP Ratings
SERP Comments:
This compound led to significant milestones relating to the role of HER3 in proliferation; however, it is a biochemical tool for covalent modification of its target. Despite successful target engagement by TX1-85-1, cell proliferation and HER3-dependent functions, including phosphorylation of downstream effector AKT, are not affected in PC9 lung carcinoma cell lines. It is not appreciably active in cells, has off-target effects (likely due to the acrylamide moiety) and is not appropriate for animal studies.
(last updated: 17 Jun 2016 )
SERP Ratings
SERP Comments:
This work develops covalent inhibitor of HER3 receptor pseudokinase, which mediates resistance to EGFR inhibitors. The covalent inhibitor targets Cys721 of HER3 and shows time- and dose-dependent inhibition of HER3 kinase. It also reversibly inhibits LYN, HER2 and SRC-family kinases. However, this paper also shows that TX1-85-1 does not inhibit HER3 signaling at 5 uM in EGFR-driven PC9 GR4 cells, and the EC50 for this compound in three EGFR-driven cell lines (PC9 GR4, HCC827 GR6, and Ovcar8) was ~10 uM. I would like to point out that the recent work by Cravatt and co-workers (Nat Chem Biol. 2014 Sep;10(9):760-7. A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors.) indicates that covalent kinase inhibitors with acrylamide electrophiles label their target kinases selectively at low doses, but at higher doses they begin to label other cysteines or perhaps other nucleophilic residue containing proteins non-specifically and this contributes to the phenotype. This was observed for both alkyne-tagged, covalent EGFR inhibitors and BTK inhibitors such as ibrutinib. In both cases substantial off-target labeling of cellular proteins was observed at 10 uM concentration of the covalent inhibitors. For this covalent inhibitor to be useful, proteomic experiments are needed to confirm target engagement in intact cells, its potency needs to be improved, and the selectivity window at which non-specific covalent labeling proteins is observed needs to be established.
(last updated: 21 Jun 2016 )