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

Abstract

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.

Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa

“…The library within which the compounds reported in this study were discovered was formed from the diverse components of primary amines and carboxylates/sulfonyl chlorides/isocyanates. This library comprises 3.76 million different compounds and has been previously reported . A cluster of structurally related coenriched building blocks in one library was identified, comprising a wide range of substituted phenyl thio acetamides and phenoxy acetamides with a smaller range of 4-tetrahydropyran-4-phenyl methylene and 4-morpholin-4-yl-phenyl methylene and similar substituents connected to the acetamide nitrogen.…”

Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit

“…LCMS (Formic, ES + ): t R = 0.86 min, [M + H] + = 384.3. N-(2-Ethoxy-2-phenylethyl)-1,5-dimethyl-N-(2-(methylamino)-2oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (45). A solution of 2-ethoxy-2-phenylethan-1-amine (109 mg, 0.658 mmol), paraformaldehyde (35.9 mg, 1.20 mmol), 1,5-dimethyl-6-oxo-1,6dihydropyridine-3-carboxylic acid (100 mg, 0.598 mmol), and isocyanomethane (0.063 mL, 1.20 mmol) in MeOH (1.5 mL) with a spatula of activated molecular sieves was stirred at 100 °C for 1 h under microwave irradiations and then was cooled to rt and diluted with water.…”

“…A DEL is composed of chimeric molecules, each containing a small molecule covalently attached to a unique DNA tag that uniquely identifies the structure of the small molecule. − The screening of DELs via an affinity selection is becoming an important source for identifying novel small molecule hits for various therapeutic targets. − Because of the advancement of next-generation DNA-sequencing technology (NGS), billions of DEL molecules can be screened easily in a single tube and in a cost-effective manner . The convenience of a DEL affinity selection also makes it possible to perform the DEL selection in a multiplex fashion, where multiple conditions are run simultaneously (e.g., different buffer conditions, different proteins as counter screens, with or without known ligands) in order to identify ligands of a desired mode of action …”

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

“…One of the compounds prioritized for synthesis without the encoding tags was 3 (Figure 2a), which was derived from a library of 3.76 million compounds with two diversity cycles of chemistry. 50 Compound 3 showed a biochemical IC 50 value of 1.3 μM, was assumed to be a type I binder according to its DEL selection profile, and served as a starting point for subsequent structure−activity relationship (SAR) exploration. It was hypothesized that the amide carbonyl and the pyrrole NH interact with the hinge region of TAK1 while the pyrrolidine ring makes hydrophobic interactions in the back pocket.…”