Cyrille Kuhn

Tetrahydroquinoline derivatives as CRTH2 antagonists

A series of tetrahydroquinoline-derived inhibitors of the CRTH2 receptor was discovered by a high throughput screen. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent and orally bioavailable CRTH2 antagonists.

Selectivity-determining residues in Plk1.

Polo‐like kinase 1 is an important regulator of cell cycle progression whose over‐expression is often associated with oncogenesis. Polo‐like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo‐like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo‐like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo‐like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co‐crystal structure of Polo‐like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non‐Polo‐like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo‐like kinase 1. The work presented here provides a framework for structure‐based drug design of Polo‐like kinase 1‐specific inhibitors.

Bipiperidinyl carboxylic acid amides as potent, selective, and functionally active CCR4 antagonists.

A cell‐based assay for the chemokine G‐protein‐coupled receptor CCR4 was developed, and used to screen a small‐molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.

Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters.

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.

The Design, Synthesis and Potential Utility of Fluorescence Probes that Target DFG-out Conformation of p38alpha for High Throughput Screening Binding Assay.

The design, synthesis and utility of fluorescence probes that bind to the DFG‐out conformation of p38α kinase are described. Probes that demonstrate good affinity for p38α, have been identified and one of the probes, PF‐04438255, has been successfully used in an high throughput screening (HTS) assay to identify two novel non‐classical p38α inhibitors. In addition, a cascade activity assay was utilized to validate the selective binding of these non‐classical kinase inhibitors to the unactive form of the enzyme.

Selective cell adhesion inhibitors: Barbituric acid based α4β7—MAdCAM inhibitors

A novel series of barbituric acid derivatives were identified as selective inhibitors of alpha4beta7 MAdCAM (mucosal addressin cell adhesion molecule-1) interactions via a high throughput screening exercise. These inhibitors were optimized to submicromolar potencies in whole cell adhesion assays, retaining their selectivity over alpha4beta1 VCAM.

Efficient Use of the Iron Ortho-Nitrophenylporphyrin Chloride to Mimic Biological Oxidations of Dimethylaminoantipyrine

Major metabolites of dimethylaminoantipyrine have been synthesized using iron ortho‐nitrophenylporphyrin chloride as biomimetic catalyst. Reactivity of iron tetrakis‐ortho‐nitrophenylporphyrin chloride [Fe(TNO2PP)Cl] has been compared with iron tetrakis‐pentafluorophenylporphyrin chloride and iron tetrakis‐2,6‐dichlorophenylporphyrin chloride using various oxidants such as hydrogen peroxide, iodosobenzene, and cumene hydroperoxide in either protic or aprotic solvent. Effect of imidazole has been showed on the reactivity of Fe(TNO2PP)Cl/cumene hydroperoxide system.

Potent and selective thiophene urea-templated inhibitors of S6K.

S6K1 (p70 S6 kinase-1) is thought to play a critical role in the development of obesity and insulin resistance, thus making it an attractive target in developing medicines for the treatment of these disorders. We describe a novel thiophene urea class of S6K inhibitors. The lead matter for the development of these inhibitors came from mining the literature for reports of weak off-target S6K activity. These optimized inhibitors exhibit good potency and excellent selectivity for S6K over a panel of 43 kinases.

Selectivity-determining Residues in Plk1: Selectivity-determining Residues in Plk1

Polo‐like kinase 1 is an important regulator of cell cycle progression whose over‐expression is often associated with oncogenesis. Polo‐like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo‐like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo‐like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo‐like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co‐crystal structure of Polo‐like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non‐Polo‐like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo‐like kinase 1. The work presented here provides a framework for structure‐based drug design of Polo‐like kinase 1‐specific inhibitors.

Research Article: Selectivity-determining Residues in Plk1

Polo‐like kinase 1 is an important regulator of cell cycle progression whose over‐expression is often associated with oncogenesis. Polo‐like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo‐like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo‐like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo‐like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co‐crystal structure of Polo‐like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non‐Polo‐like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo‐like kinase 1. The work presented here provides a framework for structure‐based drug design of Polo‐like kinase 1‐specific inhibitors.