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Davis et al . extend their previous efforts to use inhibitor-kinase interactions to understand kinase inhibitor selectivity by profiling the binding of 72 kinase inhibitors to 442 human kinase catalytic domains. The data reveal group-specific differences in selectivity and suggest the feasibility of developing reasonably specific inhibitors for most kinases. We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.

Kinases are a widely targeted enzyme class in cancer chemotherapy. Several clinically used kinase inhibitors also inhibit bromodomains, epigenetic ‘readers’ of acetylated lysine residues, suggesting that kinase-bromodomain polypharmacology may offer benefits in therapeutic settings. Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets 1 , 2 . The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome 2 , 3 , 4 . We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Nat. Chem. Biol. 10, 305–313 (2014); published online 2 March 2014; corrected after print 4 April 2014 In the version of this paper originally published, funding from the Wellcome Trust to P.F. and S.P. was not acknowledged. The acknowledgments have been corrected in the HTML and PDF versions of thearticle.

Drug discovery targeting SH2 domains (key protein-protein interaction modules) has been hampered by a lack of assay systems evaluating synthetic ligand binding selectivity toward SH2 domains, to reduce potential off-target effects. In addition, the molecular determinants for synthetic ligand engagement to SH2 domains across the target class have yet to be defined. Here, we developed SH2scan, a high-throughput competition binding assay platform to quantify ligand-SH2 domain interactions, covering >80% of the target class. We uncovered unique binding selectivity profiles and quantified a broad range of dissociation constants (KDs) for 9 synthetic ligands of SH2 domains from the scientific literature with a range of reported primary targets. These results demonstrate that SH2scan can be used to design more selective compounds targeting SH2 domains. The platform can be further leveraged for the discovery of new molecular probes for the dissection of cellular protein-protein interaction networks.

KRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance. Here, we describe the development of a new panel of biochemical and cell-based assays to evaluate the binding and function of known chemical entities targeting mutant KRAS. Our assay panels generated selectivity profiles and quantitative binding interaction dissociation constants for small molecules and degraders against wild type, G12C, G12D, and G12V KRAS, which were congruent with published data. These assays can be leveraged for additional mutants of interest beyond those described in this study, using both overexpressed cell-free systems and cell-based systems with endogenous protein levels.

We show that in the presence of large scale primordial hypermagnetic fields, it is possible to generate a large amount of CP violation to explain the baryon to entropy ratio during the electroweak phase transition within the standard model. The mechanism responsible for the existence of a CP violating asymmetry is the chiral nature of the fermion coupling to the background field in the symmetric phase which can be used to construct two-fermion interference processes in analogy to the Bohm-Aharanov effect. We estimate that for strong hypermagnetic fields B_Y=(0.3-0.5)T^2 the baryon to entropy ratio can be rho_B/s=(3 - 6)X10^-11 for slowly expanding bubble walls.

We study the scattering of fermions off a finite width kink wall during the electroweak phase transition in the presence of a background hypermagnetic field. We derive and solve the Dirac equation for such fermions and compute the reflection and transmission coefficients for the case when the fermions move from the symmetric to the broken symmetry phase. We show that the chiral nature of the fermion coupling with the background field in the symmetric phase generates an axial asymmetry in the scattering processes. We discuss possible implications of such axial charge segregation for baryon number generation.