Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

Goedken, Eric R.; Argiriadi, M.A.; Banach, David; Fiamengo, Bryan A.; Foley, Sage E.; Frank, Kristine E.; George, Jonathan S.; Harris, Christopher M.; Hobson, Adrian D.; Ihle, David C.; Marcotte, D.J.; Merta, Philip J.; Michalak, Mark; Murdock, Sara; Tomlinson, Medha J.; Voss, Jeffrey W.

doi:10.1074/jbc.m114.595181

Cited by 84 publications

(76 citation statements)

References 61 publications

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“…Detailed descriptions of these methods are included in Supplementary Data S1. Methods for high-content imaging of Cryptosporidium proliferation in HCT-8 cells (Love et al, 2017), QPatch hERG (Danker and Moller, 2014), rat cardiovascular screening (Banfor et al, 2016), in vitro micronucleus assay (Nicolette et al, 2011), the 24-well Ames screening assay, kinome profiling (Goedken et al, 2015), Nluc C. parvum in infected adult IFN-γ KO mouse efficacy (Hulverson et al, 2017), Gastroplus (Simulations Plus, Inc., Lancaster, CA, USA) modelling of efficacy and GI tissue and lumen exposures (Arnold et al, 2017), and IOWA-II strain C. parvum in infected neonatal calf efficacy (Schaefer et al, 2016) have all been previously described. All LC-MS/MS analytes were measured with an Acquity ultra performance liquid chro6 matography (UPLC) system in tandem with a Xevo TQ-S mass spectrometer (Waters, Milford, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Hulverson

Choi

Arnold

et al. 2017

International Journal for Parasitology

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Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.

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Section: Methodsmentioning

confidence: 99%

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Hulverson

Choi

Arnold

et al. 2017

International Journal for Parasitology

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“…The methyl group of the piperidine ring occupies a small hydrophobic pocket in the C-lobe ( Figure 5C,D). Compounds with better selectivity toward JAK3 and reduced side effects are currently being investigated as the next-generation JAK inhibitors [46,47].…”

Section: Dasaɵnibmentioning

confidence: 99%

FDA-approved small-molecule kinase inhibitors

Nielsen

Clausen

2015

Trends in Pharmacological Sciences

818

728

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Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure-activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.

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“…However, no reversible, isoform-specific inhibitors exist. JAK3 is the only JAK that contains a cysteine (Cys909) at the EGFR and BTK site, and was therefore targeted with tricyclic JAK inhibitors that included a terminal electrophile designed to irreversibly react with JAK3 Cys909 [26]. These compounds inhibited JAK3 with <100 nM potency in cells and selectively ablated JAK3-dependent signaling pathways, with little to no JAK2 activity up to 50 µM.…”

Section: Improving Drug Properties For Known Scaffoldsmentioning

confidence: 99%

“…These compounds inhibited JAK3 with <100 nM potency in cells and selectively ablated JAK3-dependent signaling pathways, with little to no JAK2 activity up to 50 µM. However, Goedken and colleagues reported poor pharmacokinetic profiles for these JAK3 compounds [26], and more optimization is necessary before JAK3 inhibitors catch up to their EGFR or BTK counterparts.…”

Section: Improving Drug Properties For Known Scaffoldsmentioning

confidence: 99%

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

Hallenbeck¹,

Turner²,

Renslo³

et al. 2016

CTMC

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The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an ‘allele specific’ manner. For the medicinal chemist, the structure-guided design of cysteine-reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteine-modifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues.

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Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

Cited by 84 publications

References 61 publications

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

FDA-approved small-molecule kinase inhibitors

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

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