Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing.

The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e.

Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration.

Osteoarthritis (OA) is a chronic and degenerative joint disease affecting more than 500 million patients worldwide with no disease-modifying treatment approved to date. Several publications report on the transforming growth factor β-activated kinase 1 (TAK1) as a potential molecular target for OA, with complementary anti-catabolic and anti-inflammatory effects. We report herein on the development of TAK1 inhibitors with physicochemical properties suitable for intra-articular injection, with the aim to achieve high drug concentration at the affected joint, while avoiding severe toxicity associated with systemic inhibition.

Discovery and Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors.

IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects.

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens. Despite advances in treatment with immune checkpoint inhibitors, there is an unmet need in the treatment of MSI cancers. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy.