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Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.

Following the sequencing of the human genome, data-mining efforts have revealed the existence of a new histamine receptor that is expressed at high levels in mast cells and leukocytes. The histamine H 4 receptor has a distinct pharmacological profile and the first compounds that act selectively on the H 4 receptor have been developed. Initial experiments in vivo with H 4 receptor antagonists indicate a role for the H 4 receptor in inflammatory conditions.

Following the sequencing of the human genome, data-mining efforts have revealed the existence of a new histamine receptor that is expressed at high levels in mast cells and leukocytes. The histamine H(4) receptor has a distinct pharmacological profile and the first compounds that act selectively on the H(4) receptor have been developed. Initial experiments in vivo with H(4) receptor antagonists indicate a role for the H(4) receptor in inflammatory conditions.

In the article by Leurs et al. ‘En route to new blockbuster anti-histamines: surveying the offspring of the expanding histamine receptor family’, which was published in the April 2011 issue of Trends in Pharmacological Sciences, there are two errors in Figure 2. First, compound ADP-916 should be listed APD916. Second, the Thomson Reuters Pharma database should be listed as the source for the structures of compounds HPP404 and APD916 (both retrieved Sept. 2010). In the section ‘Narcolepsy’, compound ADP-916 should also be correctly named as APD916. Trends in Pharmacological Sciences and the authors apologize to the readers for these errors.

With the recognition of two new histamine receptors at the start of the new millennium, the field of histamine research has seen a clear revival. In the last 10 years, many academic and industrial groups have taken up the challenge to target these new members of the aminergic G-protein-coupled receptor (GPCR) family. Histamine receptor research nicely illustrates how GPCR research has changed in the post-genomic era. There is a growing understanding of GPCR structure, function and modulation at a molecular level. Emerging concepts such as receptor isoforms, GPCR oligomerization and ligand-biased signaling are all being studied, but their clinical relevance remains to be determined. The histamine H 3 and H 4 drug development programs can help to establish the link between these molecular features and clinical efficacy. Several new anti-histamines are now being tested for diverse clinical applications and are poised to become the next blockbuster drugs targeting histamine receptors.