Design of a potent and selective dual JAK1/TYK2 inhibitor.

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T1 and T17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases.

Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases.

IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases.

Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R.

Autotaxin facilitates selective LPA receptor signaling.

Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA) and P2Y (LPA) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis.

Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases.

Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR.

Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis.

IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor.

The whole-genome landscape of medulloblastoma subtypes.

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets.

Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation.

Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy. Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU).

GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy.

Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.

Time-lapse imaging of neuroblastoma cells to determine cell fate upon gene knockdown.

Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma.

Androgen replacement therapy improves function in male rat muscles independently of hypertrophy and activation of the Akt/mTOR pathway.

Aim: We analysed the effect of physiological doses of androgens following orchidectomy on skeletal muscle and bone of male rats, as well as the relationships between muscle performance, hypertrophy and the Akt/mammalian target of rapamycin (mTOR) signalling pathway involved in the control of anabolic and catabolic muscle metabolism.

Methods: We studied the soleus muscle and tibia from intact rats (SHAM), orchidectomized rats treated for 3 months with vehicle (ORX), nandrolone decanoate (NAN) or dihydrotestosterone (DHT).

Results: Orchidectomy had very little effect on the soleus muscle.