Entries by webadmin

Lebraud et al., “A highly potent clickable probe for cellular imaging of MDM2 and assessing dynamic responses to MDM2-p53 inhibition.” Bioconjugate Chemistry 2018 (ahead of print), ; DOI: 10.1021/acs.bioconjchem.8b00315

Abstract MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein’s transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function […]

Heightman et al., “Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.” J. Med. Chem. 2018 61, 11, 4978-4992, ; DOI: 10.1021/acs.jmedchem.8b00421

Abstract Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates […]

Agni Gavriilidou et al., “Advancing Life Sciences R&D 2018 Online, Application of Native ESI-MS to Characterize Interactions between Compounds Derived from Fragment-Based Discovery Campaigns and Two Pharmaceutically Relevant Proteins.” SLAS Discovery, DOI: 10.1177/2472555218775921

Abstract Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits […]

2018: ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.

Abstract Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. […]

Astex’s Harren Jhoti Made Fellow of the Royal Society

Astex Pharmaceuticals (“Astex”), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that Harren Jhoti Ph.D., co-founder of Astex and President and CEO of Astex Pharmaceuticals (UK) has been elected a Fellow of the Royal Society in recognition of his […]

Rees et al. “Organic synthesis provides opportunities to transform drug discovery.” Nature Chemistry (vol 10) Apr 2018, 383-394, doi:10.1038/s41557-018-0021-z

Abstract Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges […]

Astex Continues to Deliver in Oncology as Erdafitinib, a Potential New Treatment for Metastatic Urothelial Cancer, Receives US FDA Breakthrough Therapy Designation

Astex Pharmaceuticals (“Astex”), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that its pharmaceutical collaborator, Janssen Pharmaceutica N.V. (Janssen), has been granted Breakthrough Therapy Designation by the US FDA for erdafitinib in the treatment of metastatic urothelial cancer. Erdafitinib was discovered by Astex and Janssen as part of a 2008 exclusive worldwide collaboration and licence agreement to identify novel, small […]

Harren Jhoti Receives Lifetime Achievement Award from the UK BioIndustry Association

Astex Pharmaceuticals (“Astex”), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that Harren Jhoti Ph.D., co-founder of Astex and President and CEO of Astex Pharmaceuticals (UK) has been honoured with a Lifetime Achievement Award from the UK BioIndustry […]

Tisi et al., “Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.” ACS Chem. Biol., 2016, 11 (11), pp 3093–3105, DOI: 10.1021/acschembio.6b00308

Abstract The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using […]

Johnson et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2015.” J. Med. Chem., 2017, 60 (1), pp 89–99, DOI: 10.1021/acs.jmedchem.6b01123

Abstract Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will […]