ABSTRACT
A growing number of early discovery collaborative agreements are being put in place between large pharma companies and partners in which the rights for assets can reside with a partner, exclusively or jointly. Our corporate screening collection, like many others, was built on the premise that compounds generated in-house and not the subject of paper or patent disclosure were proprietary to the company. Collaborative screening arrangements and medicinal chemistry now make the origin, ownership rights and usage of compounds difficult to determine and manage. The Compound Passport Service is a dynamic database, managed and accessed through a set of reusable services that borrows from social media concepts to allow sample owners to take control of their samples in a much more active way.
Subject(s)
Databases, Pharmaceutical , Drug Discovery/organization & administration , Drug Industry/organization & administration , Chemistry, Pharmaceutical/methods , Cooperative Behavior , Humans , Ownership , Social MediaABSTRACT
Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.
Subject(s)
Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/metabolism , SOS1 Protein/metabolism , Small Molecule Libraries/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Mutation/genetics , Protein Binding/drug effects , Protein Conformation , Proto-Oncogene Proteins p21(ras)/genetics , SOS1 Protein/chemistry , Small Molecule Libraries/chemistryABSTRACT
Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the ß-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the ß-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.
Subject(s)
1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , Inositol Phosphates/antagonists & inhibitors , Neoplasms/drug therapy , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphatidylinositol Phosphates/metabolism , Protein Kinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Cell Proliferation/drug effects , High-Throughput Screening Assays , Humans , Inositol Phosphates/metabolism , Models, Molecular , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
The oxidation of a range of cyclic allylic alcohols and amides with OsO4/TMEDA is presented. Under these conditions, hydrogen bonding control leads to the (contrasteric) formation of the syn isomer in almost every example that was examined. Evidence for the bidentate binding of TMEDA to OsO4 is presented and a plausible mechanism described.
