So, the New Year isn’t so new any more and we can all move on with getting back to the business of researching and making drugs. Looking through the articles that we have published in the last few years, one of the hot topics is that of PROTACS. In a nutshell PROTACS are PROteolysis-TArgetingChimeraS which offer a novel approach to exploring target space that in normal circumstances could not be modulated by a conventional small organic molecular approach and they do so by harnessing a degradation-based approach. In this newsletter, I’m highlighting three short articles that serve to indicate the potential of the approach for a number of therapeutic areas.
The first article, “Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective” is by Andy Pike, Beth Williamson, Stephanie Harlfinger, Scott Martin and Dermot F. McGinnity of AstraZeneca who highlight how a DMPK perspective can be used to optimize a range of molecules in their oncology portfolio. They also point out and dispel some of the myths surrounding the perceived PK issues involved in developing this class of drugs.
The next article, by Giuseppe Ermondi, Maura Vallaro and Giulia Caron: “Degraders early developability assessment: face-to-face with molecular properties” in some respect leads on from the first in that it covers the issues that such large, flexible molecules with respect to their bioavailability and other properties. Such molecular properties are difficult to estimate by in silico methods, developed for other, more orthodox entities. The article deals with approaches to allow the estimation of such properties and how methods can be developed for such degrader molecules.
Finally comes the Editorial: “Could PROTACs Protect Us From COVID-19?” by Wilnelly Martinez-Ortiz and Ming-Ming Zhou from the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The authors speculate that PROTACS, low-cost, low toxicity molecules could be effective if administered prophylactically in reducing viral infection and enhancing degradation and boosting immune response. It remains to be seen whether such an approach may result in drugs against viral infection in general and COVID-19 in particular.
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.