Hidradenitis suppurativa: new insights into disease mechanisms and an evolving treatment landscape.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic disabling and debilitating inflammatory disease with a high unmet medical need. The prevalence of HS reported in most studies is 1-2%, although it is likely to be under-reported and estimates vary globally owing to variance in data collection methods, ethnicity, geographical location and under-diagnosis. HS is characterized by persistent, painful cutaneous nodules, abscesses and draining tunnels commonly affecting the axillary, anogenital, inguinal and perianal/gluteal areas. Over time, chronic uncontrolled inflammation results in irreversible tissue destruction and scarring. Although the pathophysiology of HS has not been fully elucidated, the tumour necrosis factor (TNF)-α and interleukin (IL)-17 pathways have an important role, involving multiple cytokines. Currently, treatment options include topical medications; systemic therapies, including repeated and/or rotational courses of systemic antibiotics, retinoids and hormonal therapies; and various surgical procedures. The anti-TNF-α antibody adalimumab is currently the only biologic approved by both the US Food and Drug Administration and the European Medicines Agency for HS; however, its efficacy varies, with a clinical response reported in approximately 50% of patients in phase III trials. HS is a rapidly evolving field of discovery, with a diverse range of agents with distinct mechanisms of action currently being explored in clinical trials. Several other promising therapeutic targets have recently emerged, and agents targeting the IL-17 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are the most advanced in ongoing or completed phase III clinical trials. Alongside limited therapeutic options, significant challenges remain in terms of diagnosis and disease management, with a need for better treatment outcomes. Other unmet needs include significant diagnostic delays, thus missing the therapeutic 'window of opportunity'; the lack of standardized outcome measures in clinical trials; and the lack of established, well-defined disease phenotypes and biomarkers.

Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ.

Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.

Mature human neutrophils constitutively express the transcription factor EGR-1.

The immediate early response gene, Early Growth Response 1 (EGR-1) has emerged as a central regulator of early inflammatory and immune processes by rapidly regulating the transcription of a wide array of downstream effector genes. Neutrophils, which are among the first circulating leukocytes to respond to inflammatory signals, exhibit a broad set of transcriptional changes immediately upon exposure to inflammatory and pathogenic stimuli. Such transcriptional changes are likely to be controlled by early gene transcription factors such as EGR-1. We therefore examined the regulation and role of EGR-1 in mature human neutrophils exposed to the inflammatory stimuli fMLP and IL-8. We report that human neutrophils rapidly and transiently up-regulate EGR-1 mRNA upon stimulation with fMLP or IL-8. However in contrast to that seen in other cells, EGR-1 mRNA expression profiles were not predictive of protein expression. Instead, we show that human neutrophils constitutively express EGR-1 protein. The cellular content of EGR-1 did not change over time or upon neutrophil activation. Confocal microscopy revealed that EGR-1 was present in both the cytoplasm and nuclei of un-stimulated neutrophils and that activation did not change this subcellular localization or promote nuclear translocation. Using chromatin immunoprecipitation, we demonstrate that EGR-1 is associated with the promoter regions of the immune regulatory genes IL-1 beta, TGFbeta-1 and MIF in both resting and activated neutrophils with increased promoter association observed upon cell activation. This novel pattern of EGR-1 protein expression may underlie the ability of the neutrophil to respond rapidly to inflammatory stimuli.