Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity

Walker, Daniel P.; Zawistoski, Michael P.; McGlynn, Molly A.; Li, Jiancheng; Kung, Daniel W.; Bonnette, Peter C.; Baumann, Amy; Buckbinder, Leonard; Houser, Janet A.; Boer, Jason; Mistry, Anil; Han, Seungil; Li, Xing; Guzmán-Pérez, Angel

doi:10.1016/j.bmcl.2009.04.093

Cited by 69 publications

(36 citation statements)

References 23 publications

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“…For instance, in agricultural chemistry it was discovered that sulfoximines can improve plant growth or act as insecticides in crop protection [5–9]. Further exemplary contributions come from medicinal chemistry where sulfoximines show potential as enzyme inhibitors [10–14], and from materials science where they were evaluated as functional building blocks [15]. In addition, sulfoximines are most present in synthetic organic chemistry for various reasons and recent findings include their use as fluoromethylation reagents, as fluorophores or as directing groups [16–19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

Frings¹,

Thomé²,

Bolm³

2012

Beilstein J. Org. Chem.

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SummaryFor the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thiourea-type backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment.

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Section: Introductionmentioning

confidence: 99%

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

Frings¹,

Thomé²,

Bolm³

2012

Beilstein J. Org. Chem.

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“…To enhance the sampling of the target conformational space, four different Pyk2 kinase domain crystallographic structures with unique conformations were processed and prepared for in silico screening. The four crystal structures represent different conformations that were induced by ligands that have different selectivity profiles: 1) 3FZO is the apo, unbound state;19 2) 3FZR adopts an active conformation state (DFG-in) and contains an ATP-mimetic inhibitor, PF-431396, with a low selectivity to Pyk2;19 3) 3FZT adopts an inactive conformation (DFG-out) and contains an allosteric inhibitor, PF-4618433, selective to Pyk2;19 and 4) 3H3C adopts an active form (DFG-in) and contains the inhibitor N -methylsulfonamide 2a, which is selective to Pyk2 20. The two-dimensional interaction plots of the ligands are presented in Figure S1.…”

Section: Resultsmentioning

confidence: 99%

“…To support the goodness of predictive docking screens, enrichment experiments were carried out. First, we collected a dataset comprising 124,000 decoys from the Directory of Useful Decoys (DUD) database50 and 18 actives known from the literature20 via Konstanz Information Miner (KNIME). In addition, we collected another dataset containing 800 decoys generated by the DUD-enhanced (DUD-E) server51 based on the 18 actives.…”

Section: Resultsmentioning

confidence: 99%

“…Four high-resolution crystal structures of human Pyk2 kinase domain with distinct conformations of the active site and activation loop were selected for our high-throughput in silico screening: 1) apo-Pyk2 (Protein Data Bank [PDB] ID: 3FZO); 2) Pyk2 in complex with the inhibitor PF-431396 (PDB ID: 3FZR); 3) Pyk2 in complex with the inhibitor PF-4618433 (PDB ID: 3FZT);19 and 4) Pyk2 in complex with N -methylsulfonamide 2a (PDB ID: 3H3C) 20. The resolutions of the target PDB structures 3FZO, 3FZR, 3FZT, and 3H3C were 2.2, 2.7, 1.95, and 2.0 Å, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Despite significant efforts to develop a potent and selective inhibitor for Pyk2 over the last several years, the available inhibitors for Pyk2 lack the potency, selectivity, or have impaired pharmacokinetics,19,20 and no selective inhibitor has yet proceeded beyond pre-clinical trials, including Pfizer’s lead compound ( S )-14a from the series of sulfoximine-substituted molecules. In spite of its increased selectivity for Pyk2 over FAK, N -methylsulfoximine ( S )-14a lacks sufficient metabolic stability and is characterized by high in vivo clearance in rats 20…”

Section: Introductionmentioning

confidence: 99%

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An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2

Meirson

Samson

Gil-Henn

2017

DDDT

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The non-receptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) is a critical mediator of signaling from cell surface growth factor and adhesion receptors to cell migration, proliferation, and survival. Emerging evidence indicates that signaling by Pyk2 regulates hematopoietic cell response, bone density, neuronal degeneration, angiogenesis, and cancer. These physiological and pathological roles of Pyk2 warrant it as a valuable therapeutic target for invasive cancers, osteoporosis, Alzheimer’s disease, and inflammatory cellular response. Despite its potential as a therapeutic target, no potent and selective inhibitor of Pyk2 is available at present. As a first step toward discovering specific potential inhibitors of Pyk2, we used an in silico high-throughput screening approach. A virtual library of six million lead-like compounds was docked against four different high-resolution Pyk2 kinase domain crystal structures and further selected for predicted potency and ligand efficiency. Ligand selectivity for Pyk2 over focal adhesion kinase (FAK) was evaluated by comparative docking of ligands and measurement of binding free energy so as to obtain 40 potential candidates. Finally, the structural flexibility of a subset of the docking complexes was evaluated by molecular dynamics simulation, followed by intermolecular interaction analysis. These compounds may be considered as promising leads for further development of highly selective Pyk2 inhibitors.

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Synthesis of Sulfoximines and Sulfilimines with Aryl and Pyrazolylmethyl Substituents

et al. 2010

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Sulfoximines bearing pyrazolylmethyl and aryl substituents, which are relevant to the crop protection industry, and their corresponding sulfil-A C H T U N G T R E N N U N G imine intermediates, have been prepared from sulf-A C H T U N G T R E N N U N G ide precursors by either iron-catalyzed nitrogen transfer reactions or metal-free imination procedures. Whereas the former approach leads to Nnosyl-substituted products, the latter affords Ncyano derivatives.Keywords: heterocycles; imination; iron catalysis; metal-free conditions; sulfoximines Sulfoximines have been widely used as building blocks for the synthesis of chiral ligands [1] and pseudopeptides, [2] and they are of increasing interest due to their potential as bioactive molecules. [3,4] Although a number of synthetic approaches for the preparation of sulfoximines have been described, [5] the synthesis of derivatives with heteroaryl and, in particular, arylmethyl substituents remains highly challenging. Sulf-A C H T U N G T R E N N U N G oximines containing pyrazolylmethyl groups, and Ncyano substituents (such as A and B, respectively, Figure 1) are of particular interest to the crop protection industry.[3]Herein, we report the development of two synthetic approaches towards sulfoximines with such substitution patterns.Initially, two routes were envisaged for the preparation of aryl pyrazolylmethyl sulfoximines 2 and 3 (Scheme 1): firstly, a straightforward iron-catalyzed imination of sulfoxides 1 which was recently developed within our laboratories [route A, to give 2 (X = SO 2 R)] [6][7][8] and, secondly, a metal-free approach employing an NBS-mediated sulfur imination of sulfides 4 with cyanogen amine followed by oxidation of the resulting aryl pyrazolylmethyl sulfilimines 5 [route B, to give 3 (X = CN)]. [9,10] For both approaches sulfides 4 were the key intermediates. Their synthesis began with condensation of methylhydrazine (6) with a range of b-keto esters 7a-

show abstract

Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity

Cited by 69 publications

References 23 publications

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2

Synthesis of Sulfoximines and Sulfilimines with Aryl and Pyrazolylmethyl Substituents

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