X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase

McLean, Larry R.; Zhang, Ying; Zaidi, Nisha; Bi, Xiping; Wang, Rachel; Dharanipragada, Ram; Jurcak, John G.; Gillespy, Timothy A.; Zhao, Zhicheng; Musick, Kwon; Choi, Yong‐Mi; Barragué, Matthieu; Peppard, Jane; Smicker, Matthew; Duguid, Mei; Parkar, Ashfaq A; Fordham, Jeremy; Kominos, Dorothea

doi:10.1016/j.bmcl.2012.03.016

Cited by 25 publications

(16 citation statements)

References 15 publications

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“…The ITK kinase dimers, found in five different crystal forms in the BRAF ProtCID cluster, are a reasonable hypothesis for the mechanism of homodimerization of ITK at the membrane. These ITK dimers are not discussed or annotated by the authors of these structures [67][68][69][70][71][72][73][74] . crystal forms.…”

Section: Extending Dimers With Established Biological Activity To Othmentioning

confidence: 99%

ProtCID: A data resource for structural information on protein interactions

Dunbrack

2019

Preprint

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Structural information on the interactions of proteins with other molecules is plentiful, and for some proteins and protein families, there may be 100s of available structures. It can be very difficult for a scientist who is not trained in structural bioinformatics to access this information comprehensively. Previously, we developed the Protein Common Interface Database (ProtCID), which provided clusters of the interfaces of full-length protein chains as a means of identifying biological assemblies. Because proteins consist of domains that act as modular functional units, we have extended the analysis in ProtCID to the individual domain level. This has greatly increased the number of large protein-protein clusters in ProtCID, enabling the generation of hypotheses on the structures of biological assemblies of many systems. The analysis of domain families allows us to extend ProtCID to the interactions of domains with peptides, nucleic acids, and ligands. ProtCID provides complete annotations and coordinate sets for every cluster.

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Section: Extending Dimers With Established Biological Activity To Othmentioning

confidence: 99%

ProtCID: A data resource for structural information on protein interactions

Dunbrack

2019

Preprint

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“…Recently, novel and selective thienopyrazole inhibitors of ITK were generated by combining structure‐based design and medicinal chemistry at Sanofi (Table ) (Table S2). The most potent compounds crystallized with the target kinase ITK and also with SYK . The multikinase profiling screen of tested compounds found compound 3 to be potent towards ITK, but not selective (IC 50 = 1.9 nM ITK, IC 50 = 4.4 nM SYK and IC 50 = 73.8 nM TXK), while compound 7 was more selective towards ITK (IC 50 = 0.3 nM ITK, IC 50 = 358 nM SYK and IC 50 = 77.5 nM TXK) .…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

et al. 2013

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BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.

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“…For a site of established pharmacological relevance, C797 in the human EGFR kinase, (3poz 22 ,) and the equivalent site in three other tyrosine receptor kinases (3pjc 23 , 3v5l 24 , 4rx5 25 ), a predicted reactivity colour scheme is marked on the kinase domain sequences in Fig. 3b .…”

Section: Resultsmentioning

confidence: 99%

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons

Fowler

Blanford

Visser

et al. 2017

Sci Rep

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Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine. A surprisingly large fraction of modified sites, across the three modifications, would be buried in native protein structure. Furthermore, modified cysteines are (on average) closer to lysine ubiquitinations than are unmodified cysteines, indicating that cysteine redox biology could be associated with protein degradation and degron recognition.

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X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase

Cited by 25 publications

References 15 publications

ProtCID: A data resource for structural information on protein interactions

ProtCID: A data resource for structural information on protein interactions

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons

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