Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis.

In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.

Differences in the transactivation domains of p53 family members: a computational study.

The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population.

PURPOSE: Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors. A recent study identified mutations within the neurotrophin-4 (NTF4) gene to account for 1.7% of primary open-angle glaucoma (POAG) in Europeans. The aim of this study was to investigate the frequency of NTF4 mutations in Chinese POAG patients. METHODS: One hundred-seventy-four Chinese subjects with POAG and 91 normal Chinese subjects were recruited. POAG was defined by the presence of glaucomatous optic neuropathy, open angles on gonioscopy, and absence of secondary causes of glaucoma. The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects. RESULTS: The mean age of POAG patients was 66.0+/-13.0 years (range 25-96 years) and that of controls was 67.1+/-4.6 years (range 60-85 years). We identified a novel NTF4 missense mutation substituting leucine by serine at codon 113 (Leu113Ser) caused by a c.338T>C mutation in a single patient with unilateral POAG, who presented with a baseline intraocular pressure of 25 mmHg, a vertical cup-to-disc ratio of 0.9 and an inferior hemifield defect in the affected eye. Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB. CONCLUSIONS: Identification of a single mutation in our study suggests that NTF4 mutations are a rare cause of POAG (0.6%, 95%CI 0.02%-3.16%) in Chinese people.