Discovery of a potent and highly selective transforming growth factor β receptor-associated kinase 1 (TAK1) inhibitor by structure based drug design (SBDD)

Muraoka, Terushige; Ide, Mitsuaki; Morikami, Kenji; Irie, Masayasu; Nakamura, Mariko; Miura, Takaaki; Kamikawa, Takayuki; Nishihara, Masamichi; Kashiwagi, Hirotaka

doi:10.1016/j.bmc.2016.07.006

Cited by 12 publications

(9 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another type I inhibitor was developed by Chugai Pharmaceuticals. Optimization of a screening hit using SBDD resulted in compound 3 . The inhibitor showed good activity and excellent selectivity.…”

mentioning

confidence: 99%

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

Veerman¹,

Bruseker²,

Damen³

et al. 2021

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.

show abstract

mentioning

confidence: 99%

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

Veerman¹,

Bruseker²,

Damen³

et al. 2021

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…We had already reported novel TAK1 type I inhibitors with their X-ray information, including the complex of 1 (TAK1 IC 50 =2.3 nM) with TAK1 in the DFG-in conformation 20) (Fig. 2(a)).…”

Section: Resultsmentioning

confidence: 99%

“…20) Crystallization, Data Collection and Structure Determination The purified TAK1-TAB1 fusion protein samples were concentrated to 3 mg/mL with about 0.2 mM of each compound (2, 3, and 4), and crystallization was carried out by the hanging-drop vapor diffusion method at 20-21°C. The reservoir solution consisted of 1.7-1.9 M sodium potassium phosphate (pH 7.5-7.7).…”

Section: Methodsmentioning

confidence: 99%

“…The starting material 7 was prepared by the same procedure in our previously report. 20) Then the common intermediate 8 was synthesized by amidation reaction between 7 and commercially available 2-bromothiazole-4-carboxylic acid in 83% yield. To synthesize compound 9, Suzuki coupling between 8 and m-aminophenylboronic acid 24) was conducted to afford 9, and then the obtained compound 9 was treated with phenylisocyanate at 60°C to generate the type II inhibitor 3 as an urea compound in moderate yield (2 steps 39%).…”

Section: Chemistrymentioning

confidence: 99%

“…1). We have already reported novel type I TAK1 inhibitors and X-ray information between one of the most potent our TAK1 type I inhibitor (1) and TAK1 (PDB code: 5JGA), 20) we utilized this information to design a new type II inhibitor (3) and c-helix-out inhibitors (4, 5, and 6) by the hybridization strategy. 21,22) For the type II inhibitor, the X-ray crystal structure of 1 and 2 were superimposed to design compound 3 by modeling.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD)

Muraoka

Ide

Irie

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

We have developed a method for converting a transforming growth factor-β-activated kinase 1 (TAK1) type I inhibitor into a type II or c-helix-out inhibitor by structure-based drug design (SBDD) to achieve an effective strategy for developing these different types of kinase inhibitor in parallel. TAK1 plays a key role in inflammatory and immune signaling, and is therefore considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). We have already reported novel type I TAK1 inhibitor, so we utilized its X-ray information to design a new chemical class type II and c-helixout inhibitors. To develop the type II inhibitor, we superimposed the X-ray structure of our reported type I inhibitor onto a type II compound that inhibits multiple kinases, and used SBDD to design a new type II inhibitor. For the TAK1 c-helix-out inhibitor, we utilized the X-ray structure of a b-Raf c-helix-out inhibitor to design compounds, because TAK1 is located close to b-Raf in the Sugen kinase tree, so we considered that TAK1 would, similarly to b-Raf, form a c-helix-out conformation. The X-ray crystal structure of the inhibitors in complex with TAK1 confirmed the binding modes of the compounds we designed. This report is notable for being the first discovery of a c-helix-out inhibitor against TAK1.Key words transforming growth factor-β-activated kinase 1 (TAK1); inhibitor; type I; type II; c-helix-out; structure-based drug design Of over 500 kinases in human that maintain the functions of cells, 1) it is not completely clear which kinase inhibition causes an adverse event; therefore, it is important for kinase inhibitors to have a highly selective profile. However, in many cases, kinase inhibitors possess undesired off-target kinase activity, so multiple development candidates with different kinase selectivity profiles need to be prepared, and then a compound with a wide therapeutic window that has no severe adverse effects can be selected as a development candidate. In general, kinase inhibitors are classified into three different types 2,3) : a type I inhibitor binds to the active conformation (DFG-in conformation) of a kinase at the ATP-binding site and competes with ATP; a type II inhibitor binds to both the ATP binding site and its adjacent binding pocket in an inactive conformation (DFG-out conformation) of a kinase; a type III inhibitor is an allosteric inhibitor that has a binding site distinct from the ATP-binding site. Discovery of a type I inhibitor with high kinase selectivity is additionally challenging because amino acid residues in the ATP-binding site are highly conserved in many kinases. On the other hand, it is considered easier to identify a selective type II inhibitor because a type II inhibitor is able to utilize the lipophilic binding pocket derived from the DFG-out conformation, which is less conserved in terms of amino acid residues (though it has recently been reported that not all type II inhibitors possessed high kinase selectivity, 4) so this topic is...

show abstract

From DEL Selections to Validated Hits to Clinical Leads

Marcaurelle¹,

Tear²,

Yao³

2022

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

Discovery of a potent and highly selective transforming growth factor β receptor-associated kinase 1 (TAK1) inhibitor by structure based drug design (SBDD)

Cited by 12 publications

References 33 publications

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD)

From DEL Selections to Validated Hits to Clinical Leads

Contact Info

Product

Resources

About