Business


Figure 1 The proteasome, nuclear


factor-KB and bortezomib. The proteasome is a barrel-shaped multiprotein particle that destroys proteins that have


been marked for degradation by conjugation to ubiquitin. Binding of the transcription


factor nuclear factor-KB (NF- KB) to the inhibitor protein


IKB in the cytoplasm renders NF-KB inactive. Cellular stimuli, such as cytokines,


antigens, oxidants, viruses and


other agents, trigger a cascade of signal transduction events that phosphorylate and


ubiquitinate IKB, leading to its degradation by the


proteasome, which in turn liberates NF-KB for


translocation into the nucleus. Once in the nucleus, NF-KB


binds to the promoter regions of genes coding for proteins that are involved in the


activation of transcription, growth, angiogenesis, anti- apoptotic factors and cell- adhesion molecules. By


inhibiting the proteasome, bortezomib inhibits the


activation of NF-KB (orange crosses) and subsequent events that can promote tumour cell survival and proliferation.


Source: Sánchez-Serrano, I. Success in Translational Research:


Lessons from the Development of Bortezomib. Nature Reviews


Drug Discovery, 5 (2):107-14 (2006)


www.Openprot.org). It has already demonstrated that another body of knowledge around possible targets for drug discovery is becoming relevant and will provide a treasure trove of knowledge for future drug discovery scientists to think about and perhaps revisit fallen programmes where ‘knock- out’ data confirmed an interaction but drugging the ‘protein’ never provided the anticipated results. Lots of rationale of why the drug may not have worked, but perhaps the wrong protein was drugged. What if it was an alt-protein responsible for the effect?


Biologicals Monoclonal antibodies are the hot topic of pharma industry as these drug approvals are picking up and the ability to utilise them in CAR-T and other technologies is gaining momentum. The roots of creating and selecting these monoclonals has diverse streams, however; the common one from academia is the creation of a mouse mAb utilising hybridoma methodology as a starting point. While this has produced great tools for biology and sometimes is the starting point for development of a humanised version for drug development, we now realise that this is a tricky and complicated development path involving time-consuming


44


screening for the right potency, selectivity and ‘humanised’ lead. In the past few years, the idea has emerged to begin with fully human, not mouse, antibodies as the starting point to alleviate some of the challenges of developing drug candidates. Much like the chemists have defined useful back- bones for compound drug development, biologists have now defined a number of scaffolds based on those that have been in Phase I and combined that with V-regions and alleles that are shared by all human populations. Along with selecting specific CDR regions and creating a diversity of 76 billion Abs allows for quick selection of mAbs with high specificity and good clinical perspective. This ‘Bio Superhuman library 2.0’ – a synthetic monoclonal Ab library – claims to reduce monoclonal lead dis- covery and development to about two months (https://www.distributedbio.com).


The phoenix: core model approach to drug discovery and development Given the crucial importance of the pharmaceuti- cal industry in the world’s healthcare systems4-6, it is very surprising that little attention has been paid to the understanding of the ways in which the pharmaceutical industry has succeeded in bringing remarkable novel drugs to the market in its


Drug Discovery World Spring 2018


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72