A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Tuning a Protein‐Labeling Reaction to Achieve Highly Site Selective Lysine Conjugation

Activated esters are widely used to label proteins at lysine side chains and N termini. These reagents are useful for labeling virtually any protein, but robust reactivity toward primary amines generally precludes site‐selective modification. In a unique case, fluorophenyl esters are shown to preferentially label human kappa antibodies at a single lysine (Lys188) within the light‐chain constant domain. Neighboring residues His189 and Asp151 contribute to the accelerated rate of labeling at Lys188 relative to the ≈40 other lysine sites. Enriched Lys188 labeling can be enhanced from 50–70 % to >95 % by any of these approaches: lowering reaction temperature, applying flow chemistry, or mutagenesis of specific residues in the surrounding protein environment. Our results demonstrated that activated esters with fluoro‐substituted aromatic leaving groups, including a fluoronaphthyl ester, can be generally useful reagents for site‐selective lysine labeling of antibodies and other immunoglobulin‐type proteins.     

Electroless deposition and characterization of Ni-P-WC composite alloys

A composite coating Ni-P-WC was produced using an electroless deposition technique from citrate bath containing WC powder. The influence of plating parameters such as WC content, pH, temperature and stirring rate on the content of WC codeposited with Ni-P alloys were investigated. The maximum value of WC (50-55 V_p) codeposited can be achieved at a particle content of 20 gL^− 1 in the electrolyte, at pH 5.5-6, temperature 85-90 °C and stirring rate of 150 rpm. Surface morphology and microstructure of Ni-P-WC coatings were determined by means of SEM and X-ray diffraction. It was found that the phase structure of the solid solution cannot be varied by codeposition of WC particles in Ni-P alloys, and it only influences the growth of the crystal planes. The properties of the composite such as hardness and abrasion resistance were also examined and compared with WC free nickel deposited layer. The presence of WC particles in the deposit significantly was found to improve the hardness and abrasion resistance of composite coatings.