The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

Key Points IFN-γ alone is capable of inducing monocyte to macrophage differentiation. IFN-γ–derived macrophages present a high proinflammatory phenotype. Phenotypic characteristics of IFN-γ macrophages are expressed in patients with psoriasis. As key cells of the immune system, macrophages coordinate the activation and regulation of the immune response. Macrophages present a complex phenotype that can vary from homeostatic, proinflammatory, and profibrotic to anti-inflammatory phenotypes. The factors that drive the differentiation from monocyte to macrophage largely define the resultant phenotype, as has been shown by the differences found in M-CSF– and GM-CSF–derived macrophages. We explored alternative inflammatory mediators that could be used for in vitro differentiation of human monocytes into macrophages. IFN-γ is a potent inflammatory mediator produced by lymphocytes in disease and infections. We used IFN-γ to differentiate human monocytes into macrophages and characterized the cells at a functional and proteomic level. IFN-γ alone was sufficient to generate macrophages (IFN-γ Mϕ) that were phagocytic and responsive to polarization. We demonstrate that IFN-γ Mϕ are potent activators of T lymphocytes that produce IL-17 and IFN-γ. We identified potential markers (GBP-1, IP-10, IL-12p70, and IL-23) of IFN-γ Mϕ and demonstrate that these markers are enriched in the skin of patients with inflamed psoriasis. Collectively, we show that IFN-γ can drive human monocyte to macrophage differentiation, leading to bona fide macrophages with inflammatory characteristics.

DUAL946 (1) inhibits BET and HDAC proteins in chemoproteomic cell lysate experiments and in immune and cancer cells.

Inhaled glucocorticoids are highly effective therapies for respiratory diseases. Progress in characterising the complex molecular mechanisms that control glucocorticoid action raises the possibility that anti-inflammatory molecules with reduced side-effect liabilities can be identified. Here we describe the discovery of a novel glucocorticoid, GW 870086, with unique biological properties, and demonstrate the potential of gene expression profiling in the characterisation of its pharmacology. This molecule is under clinical evaluation as a novel respiratory agent. The pharmacological properties of GW870086 were assessed against fluticasone propionate (FP) using cellular and in vivo model systems, including extensive gene expression profiling. GW870086 repressed inflammatory cytokine release from primary lung epithelial cells with similar efficacy to FP, but in marked contrast to FP antagonised the effect of dexamethasone on MMTV driven reporter gene transactivation. GW870086 had a very significant effect on the expression of specific glucocorticoid regulated genes while having minimal impact on the expression of other known target genes, demonstrating unique regulation of gene transcription. In experimental in vivo models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation models, GW870086 showed comparable anti-inflammatory efficacy to FP. GW870086 is a potent anti-inflammatory compound that has a unique ability to regulate a specific subset of genes that are normally effected by classical glucocorticoids. It has clear potential to be developed as a new topical steroid with a distinct safety profile to existing therapies.

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC50 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.

Glucocorticoid receptor (GR) agonists have been used for more than half a century as the most effective treatment or acute and chronic inflammatory conditions despite serious side effects that accompany their extended use that include glucose intolerance, muscle wasting, skin thinning, and osteoporosis. As a starting point for the identification of GR ligands with an improved therapeutic index, we wished to discover selective nonsteroidal GR agonists and antagonists with simplified structure compared to known GR ligands to serve as starting points for the optimization of dissociated GR modulators. To do so, we selected multiple chemical series by structure guided docking studies and evaluated GR agonist activity. From these efforts we identified 5-arylindazole compounds that showed moderate binding to the glucocorticoid receptor (GR) with clear opportunities for further development. Structure guided optimization was used to design arrays that led to potent G R agonists and antagonists. Several in vitro and in vivo experiments were utilized to demonstrate that GR agonist 23a (GSK9027) had a profile similar to that of a classical steroidal GR agonist.