Lead generation fragment-based

Lead Generation Methods, Strategies, and Case Studies, First Edition. Edited by Jorg Holenz. 

Drug and latest reported development Company Target 

Notei Some of these drugs have been discontinued. Drugs highlighted in bold are believed to be still in active development, as listed on company web sites or clinicaltrials.gov. 

Because of the improved sampling of chemical space, as well as the sometimes low-throughput biophysical methods needed to detect low-affinity binders. 

A detailed description of screening methods used in FBLG is beyond the scope of this chapter many FBLG reviews are available [34-39]. We will just briefly outline some of the assays used for fi agment hit identification before exploring strategies and tactics employed in hit optimization. 

This work is a good example of where modification of a protein can be used to anchor a molecular starting point. This approach may be of particular value when targeting less tractable kinases or indeed other targets classes. Additionally, the approach utilised different forms of the target protein to look for different mechanisms of action and in this case uncovered a novel inhibitor series that preferentially binds to the unphosphorylated form of the 

Unphosporylated PDK1 IC50 0.013 pM Phosphorylated PDK1 IC50 0.002 pM Cell EC50 0.4 pM 

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An integrated approach to fragment-based lead generation philosophy, strategy and case studies from AstraZeneca s drug discovery programmes. Curr Top Med Chem 7, 1600-1629. 

Geschwindner, S., Olsson, L. L., Albert, J. S., Deinum, J., Edwards, P. D., de Beer, T., and Folmer, R. H. A. (2007). Discovery of a novel warhead against beta-secretase through fragment-based lead generation. Journal of Medicinal Chemistry 50, 5903-5911. 

Gill, A. L., et al., Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. J Med Chem, 2005, 48, 414-426. 

Edwards, P. D., et al., Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity and high ligand efficiency. J Med Chem, 2007, 50, 5912-5925. 

Identification of High-affinity P-Secretase Inhibitors Using Fragment-based Lead Generation... 

Fig. 10.5 Fragment-based lead generation. Once fragments have been identified bound into the active site they can be used as a start point for iterative structure-driven chemistry resulting in a drug-size lead compound. If two fragments are bound in 2 different pockets (a) then they could be used to decorate an appropriate scaffold (b). Alternatively, a single fragment can be rationally modified to occupy other neighbouring pockets (c).

Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, de Beer T, Folmer RH (2007) Discovery of a novel warhead against P-secretase through fragment-based lead generation. J Med Chem 50 5903-5911... 

RA Pearson, S Tart, J Tucker, J.A., Vogtherr, M Whittaker, D Wingfield, J Winter, J and Hudson, K. (2012) Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation. Journal of Medicinal Chemistry, 55 3285-3306. 

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