Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery
Abstract not provided
Yan, Xin Cindy↗
Engineering topics
Sanders, John M.
Publications and source records attributed to Sanders, John M..
Discovery of a chemical probe for PRDM9
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC 50 : 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Improved Abutting Edges For Welding In Keyhole Mode
Welds of better quality made, and/or heat input reduced. Improved shapes devised for abutting edges of metal pieces to be joined by plasma arc welding in keyhole mode, in which gas jet maintains molten hole ("keyhole") completely through thickness of weld joint. Edges of metal pieces to be welded together machined to provide required combination gap and shaped, thin sections. Shapes and dimensions chosen to optimize weld in various respects; e.g., to enhance penetration of keyhole or reduce heat input to produce joint of given thickness.
Harwing, Dennis D.↗
Reduced heat input keyhole welding through improved joint design
An improved high energy density welding method for reducing input keyhole welding prepares the weld joint (8) between two edges (10, 14) of at least one member by separating the edges (10, 14) of the member (12, 16) with a controllable gap (22) by a projecting portion (24) selectively positioned on one edge (10, 14) of the member (12, 16). The projecting portion (24) closely abuts the other edge of the member for maintaining the controlled distance (d) of the controllable gap (22) to enhance the welding method.
Sanders, John M.↗