This month’s newsletter is covering aspects of allosterism as related to drug discovery. There are a number of benefits in developing drugs that interact with an allosteric site, not least that it may allow the examination of alternative structures for chemical exploration, especially when developing drugs for the orthosteric site may be difficult or selectivity is an issue, for example when multiple receptors share a very similar binding site. Furthermore, it may be possible to avoid intrinsic toxicities that may be associated with chemical series developed for particular targets. The articles included in this newsletter cover a wide range of topics outlining allosteric drug resistance, novel allosteric therapies and a mathematical approach to quantify allosteric interactions within a receptor heterodimer.
The first article featured in this newsletter is entitled: “Emergence of allosteric drug-resistance mutations: New challenges for allosteric drug discovery.” by Shaoyong Lu, Yuran Qiu, Duan Ni, Xinheng He, Jun Pu and Jian Zhang of the Shanghai Jiao Tong University, The article deals with the development of allosteric drug resistance, reducing efficacy and utility. Such resistant mutated targets are thought to occur as a result of the lower evolutionary pressure upon allosteric sites compared with the orthosteric sites. They discuss examples of drug-resistance allosteric mutations in clinically-important targets and strategies to avoid drug resistance.
Following on from this is a more applied article, outlining progress in the development of allosteric modulators of the hypoxia-inducible factor 2α (HIF-2α). The paper, “Allosteric inhibition of HIF-2α as a novel therapy for clear cell renal cell carcinoma” by Yancheng Yu, Quanwei Yu and Xiaojin Zhang of the China Pharmaceutical University, Nanjing, China, discusses the development of a novel molecule currently in clinical trial and the role of such compounds as therapies for clear cell renal cell carcinoma. The paper gives insight into the discovery, development and mechanism of action of such allosteric modulators.
In the last free download, from Bin Zhou and Jesús Giraldo of the Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain entitled: “Quantifying the allosteric interactions within a G protein-coupled receptor heterodimer” the authors discuss a more theoretical approach to allosterism. A significant proportion of the investigation of allosterism has dealt with homologous allosteric effects. Zhou and Giraldo discuss mathematic modelling to quantify and predict the interactions in receptor heterodimers, a state that is increasingly thought to be more prevalent than was previously expected.
Steve Carney was born in Liverpool, England and studied Biochemistry at Liverpool University, obtaining a BSc.(Hons) and then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University, in the Departments of Medical Biochemistry and Histopathology. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London, where he worked with Professor Helen Muir FRS and Professor Tim Hardingham, on the biochemistry of experimental Osteoarthritis. He joined Eli Lilly and Co. and held a number of positions in Biology R&D, initially in the Connective Tissue Department, but latterly in the Neuroscience Department. He left Lilly to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. Currently, he also holds an honorary lectureship in Drug Discovery at the University of Surrey, UK. He has authored over 50 articles in peer-reviewed journals, written several book chapters and has held a number of patents.