Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure–activity relationships and strategies for the elimination of reactive metabolite formation

Walker, Daniel P.; Bi, Fangchao; Kalgutkar, Amit S.; Bauman, Jonathan N.; Zhao, Sabrina X.; Soglia, John R.; Aspnes, Gary E.; Kung, Daniel W.; Klug-McLeod, Jacquelyn; Zawistoski, Michael P.; McGlynn, Molly A.; Oliver, Robert M.; Dunn, Matthew F.; Li, Jiancheng; Richter, Daniel; Cooper, Beth; Kath, John C.; Hulford, Catherine A.; Autry, Christopher; Luzzio, Michael J.; Ung, Ethan; Roberts, W. Gregory; Bonnette, Peter C.; Buckbinder, Leonard; Mistry, Anil; Griffor, Matthew C.; Han, Seungil; Guzmán-Pérez, Angel

doi:10.1016/j.bmcl.2008.10.030

Cited by 49 publications

(29 citation statements)

References 15 publications

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“…5B). NanoBRET data were in very good agreement with previously reported IC50 values (Allen et al, 2009;Heinrich et al, 2013;Walker et al, 2008; for both FAK and PYK2. FAK in vitro selectivity for the present series of compounds was translated into the cellular context, where 5 was the most selective compound for FAK with a 330-fold difference compared to PYK2.…”

Section: Binding Potency and Kinetics Of Fak And Pyk2 In Living Cellssupporting

confidence: 90%

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Berger

Amaral

Kokh

et al. 2021

Cell Chemical Biology

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Section: Binding Potency and Kinetics Of Fak And Pyk2 In Living Cellssupporting

confidence: 90%

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Berger

Amaral

Kokh

et al. 2021

Cell Chemical Biology

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“…The FAK/Pyk2 inhibitor PF431396 was developed as an ATP mimetic and a potent pyrimidine-based inhibitor against recombinant Pyk2 (30). In vivo studies demonstrated that daily treatment of PF431396 in rats causes a significant increase in bone density (31), which also occurs in Pyk2 2/2 mice (32),…”

Section: Pf431396 Inhibits Pyk2 and Paxillin Tyrosine Phosphorylationmentioning

confidence: 99%

Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

Cheung

Ostergaard

2016

The Journal of Immunology

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Protein tyrosine kinase 2 (Pyk2) is required for T cell adhesion to ICAM-1; however, the mechanism by which it regulates adhesion remains unexplored. Pyk2 function in murine CTL clones and activated ex vivo CD8+ T cells was disrupted by pharmacological inhibition, knockdown of expression with small interfering RNA, or expression of the dominant-negative C-terminal domain. We found that Pyk2 is not absolutely required for adhesion of CTL to ICAM-1, but rather delays the initial adhesion. Disruption of Pyk2 function caused cells to display an unusual elongated appearance after 1 h on ICAM-1, consistent with abnormally strong adhesion. Furthermore, the random mobility of CTL on ICAM-1 was severely compromised using all three methods of disrupting Pyk2 function. Live-cell imaging studies revealed that the decreased migration is the result of a defect in the detachment from ICAM-1 at the trailing edge when Pyk2 function is inhibited. Examination of Pyk2 tyrosine phosphorylation in normal polarized cells demonstrated that Pyk2 phosphorylated at Y579 and Y580 preferentially localizes to the leading edge, whereas Y881-phosphorylated Pyk2 is enriched at the trailing edge, suggesting that the tyrosine phosphorylation of Pyk2 is spatially regulated in migrating CTL. Additionally, inhibition of Pyk2 caused cells to form multiple LFA-1–rich tails at the trailing edge, most likely resulting from a defect in LFA-1 release required for forward movement. Our results show that Pyk2 contributes to CTL migration by regulating detachment of CTL at the trailing edge, which could explain why Pyk2 is important for chemotactic and migratory responses.

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“…A similar strategy to mitigate the risk of toxicity is exemplified by the design of potent and safe proline‐rich tyrosine kinase 2 (PYK2) inhibitors . The lead compound in this program showed a propensity to undergo bioactivation via the formation of a quinone imine intermediate (Fig.…”

Section: Determination and Identification Of Chemically Reactive Metamentioning

confidence: 99%

The Generation, Detection, and Effects of Reactive Drug Metabolites

et al. 2012

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The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein-reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug-drug interactions that may ensue. One important class of protein-reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.

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Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure–activity relationships and strategies for the elimination of reactive metabolite formation

Cited by 49 publications

References 15 publications

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

The Generation, Detection, and Effects of Reactive Drug Metabolites

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