WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. ...Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.
Crisis and Renewal in Twentieth Century Banking explores the behaviour of banks at times of war, revolution, civil war, social turmoil, and reconstruction. Analysing the history and archives of ...banks, it discovers examples of how banking is affected by political and social upheavals; how banks may influence the outcome of such events; how banking has recovered from periods of intense political and social stress; and how the archives of banks provide remarkable testimony to events in the wider world. By examining the setting of different banking markets in the last century, up to and including the transformation of Eastern and South Eastern Europe in the 1990s, this book marks a new direction for international discussion and research. Contributors include senior historians and archivists from Europe and the United States. Contributions include papers on Russia and foreign banks, 1917-30; depression and crisis in Central Europe in the 1930s; Civil War in Spain; post-war reconstruction in banking in Germany and the Far East; and crisis and renewal in South East Europe. The papers published in this collection were first presented at the twelfth Annual Conference of the European Association for Banking History, held in Ljubljana, Slovenia, in May 2001, and hosted by the Bank of Slovenia and the Nova Ljubljanska Banka.
Contents: Introduction; Part I War and Revolution: Russian and Foreign Banks, 1917-30: A private banking house at war: Barings and Russia, 1914-17, John Orbell; Russian banks during the First World War and the Revolution, Sergej Lebedev; Witnesses to revolution: the archives of foreign banks in Russia, Catherine Potier. Part II Depression and Political Turmoil in Central Europe: Under western eyes: foreign banks' archives relating to Central and Eastern Europe between the wars, Edwin Green; Croatian banking during the 1926-36 depression, Ivo Bicanic and Zeljko Ivankovic. Part III Banking in Civil War and its Aftermath: The Republic besieged? British banks and the Spanish Civil War 1936-39, Tom Buchanan; Spanish banking after the Civil War: a halting reconstruction under Fascism, Gabriel Tortella and José L. GarcÃa-Ruiz; The transition after the civil war in Greece, Konstantinos Kostis. Part IV Post-war reconstruction: The German and Far Eastern Experience: The transformation and reconstruction of banking in Germany, 1945-57, Martin L. Müller; New political realities and the post-war re-establishment of foreign banks in East and South-East Asia, Frank H.H. King. Part V Crisis and Renewal in 20th-century Banking: the Slovenian Experience: A comparison of banking crises in Slovenia in the 1930s and 1990s, Franjo Å tiblar; Slovenian banking in transition, Ivan Ribnikar. Part VI Rupture and Reconnections: South-East European banks and Western banking: 20th-century connections and crises, John R. Lampe; Reconstructing national identities: the banknotes of Central and Eastern Europe in the 1990s, Virginia Hewitt and Tim Unwin; Index.
SETD2, a lysine N-methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that ...features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.
SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account ...details the discovery of EPZ-719, a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core. Structure-based drug design (SBDD) and drug metabolism/pharmacokinetics (DMPK) optimization resulted in EPZ-719, an attractive tool compound for the interrogation of SETD2 biology that enables in vivo target validation studies.
Indazoles are unselectively protected under strongly basic conditions to give a mixture at N-1 and N-2. Under mildly acidic conditions, regioselective protection at N-2 takes place. Thermodynamic ...conditions lead to regioselective protection at N-1. This trend applies to various substituted indazoles. Protected 5-bromoindazoles participate in Buchwald reactions with a range of amines to generate novel derivatives.
Twentieth-century Southeastern Europe endured three, separate decades of international and civil war, and was marred in forced migration and wrenching systematic changes. This book is the result of a ...year-long project by the Open Society Institute to examine and reappraise this tumultuous century.A cohort of young scholars with backgrounds in history, anthropology, political science, and comparative literature were brought together for this undertaking. The studies invite attention to fascism, socialism, and liberalism as well as nationalism and Communism. While most chapters deal with war and confrontation, they focus rather on the remembrance of such conflicts in shaping today's ideology and national identity.
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