It has been demonstrated that certain compounds bind to TNF and stabilise a conformation of trimeric TNF that binds to the TNF receptor. Antibodies which selectively bind to complexes of such compounds with TNF superfamily members are disclosed. These antibodies may be used to detect further compounds with the same activity, and as target engagement biomarker.

It has been demonstrated that certain compounds bind to TNF and stabilise a conformation of trimeric TNF that binds to the TNF receptor. Antibodies which selectively bind to complexes of such compounds with TNF superfamily members are disclosed. These antibodies may be used to detect further compounds with the same activity, and as target engagement biomarker.

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of USP30, and the treatment of USP30-mediated disorders.

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of USP30, and the treatment of USP30-mediated disorders.

A new, stable trimeric TNF structure is disclosed with distorted symmetry which can bind to the TNFR1 receptor to attenuate signalling therefrom, which can be used in the treatment and/or prevention of diseases associated with the soluble TNF/TNFR1 interaction. Membrane-bound TNF is not affected in its ability to signal through TNFR2, and thus the new structure of TNF may be used in therapies which do not significantly raise the risk of infection or malignancy.

A new, stable trimeric TNF structure is disclosed with distorted symmetry which can bind to the TNFR1 receptor to attenuate signalling therefrom, which can be used in the treatment and/or prevention of diseases associated with the soluble TNF/TNFR1 interaction. Membrane-bound TNF is not affected in its ability to signal through TNFR2, and thus the new structure of TNF may be used in therapies which do not significantly raise the risk of infection or malignancy.

The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

Disclosed herein is the compound (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one of the following structure: ##STR00001##
and/or pharmaceutically acceptable salts and/or pharmaceutical compositions thereof, which inhibit phosphatidylinositol 3-kinase (PI3K) activity.

A small molecule antagonist compound having a toll-like receptor 3/7/8/9 inhibitory function and its use in inhibiting TLR7, TLR8, TLR9 and TLR3 are disclosed. A novel compound expressed by TAC5 and TAC5-a, TAC5-c, TAC5-d or TAC5-e which are derivatives thereof not only prevents TNF secretion, NFkB activation, IkB degradation and MAPKs phosphorylation induced by poly(I:C) (TLR3 agonist), IMQ (TLR7 agonist), CL075 (TLR7/8 agonist), R848 (TLR7/8 agonist), TL8 (TLR8 agonist) or CpG ODN (TLR9 agonist), but also inhibits generation of inflammatory cytokine, and thus is highly advantageous for preventive or therapeutic use for TLR3/7/8/9-related autoimmune diseases and inflammatory diseases including systemic lupus erythematosus, psoriasis and the like.