Gerhard Müller

Second-generation kinase inhibitors.

An increasing number of kinase inhibitor candidates are entering clinical development, representing an important change in the pharmaceutical industry; notably, the development of small-molecule kinase inhibitors for signal transduction therapies. Today, kinase inhibitors garner substantial attention in cancer research. Over the last few years, three distinct small-molecule kinase inhibitors reached the market for treatment of chronic myeloid leukaemia, gastrointestinal stromal tumours, and non-small cell lung cancers. These three drugs, imatinib, gefitinib and erlotinib, act on a distinct subset of dysregulated, and often cancer-relevant kinases. Imatinib, gefitinib and erlotinib are considered the front-runners of targeted kinase inhibitor drugs. The entire research field gains tremendous insights through the ongoing research and clinical trials with these three drugs and with fast following first-generation kinase inhibitors, many of which are in different phases of clinical development. In addition, novel chemogenomic and chemoproteomic technologies are emanating from the current kinase research area, focussing efforts on the generation of spectrum-selective inhibitors for anticancer therapies as opposed to the monospecific inhibitors for the remaining therapeutic areas.

Evaluation of Kinase Inhibitor Selectivity by Chemical Proteomics

Small-molecule inhibitors of protein kinases constitute a novel class of drugs for therapeutic intervention in a variety of human diseases. Most of these agents target the relatively conserved ATP-binding site of protein kinases and have only been tested against a rather small subset of all human protein kinases. Therefore, the selectivity of protein kinase inhibitors has remained a widely underestimated, but highly important issue in drug development programs. In this review, we focus on the recent advancement of chemical proteomic methods to evaluate drug selectivity in an unbiased, comprehensive way. Efficient affinity purification procedures using immobilized kinase inhibitors combined with the sensitivity of mass spectrometry detection permit the mapping of drug targets on a proteome-wide scale. Data from this type of assessment can be used to set up tailor-made selectivity panels, which guide compound development in the context of the most relevant off-targets during lead optimization. In cases in which identified alternative targets are of validated clinical relevance, chemical proteomics provides the opportunity to repeatedly exploit a once established kinase inhibitor principle for additional target kinases and can thereby dramatically shorten the time toward highly selective, preclinical candidates. Moreover, the identification of alternative targets for preclinical or clinical drugs can provide new insights into their cellular modes of action, which might help to define those disease settings in which the most beneficial therapeutic effect is likely to occur.

Unexpected Novel Binding Mode of Pyrrolidine-Based Aspartyl Protease Inhibitors: Design, Synthesis and Crystal Structure in Complex with HIV Protease

At present nine FDA‐approved HIV protease inhibitors have been launched to market, however rapid drug resistance arising under antiviral therapy calls upon novel concepts. Possible strategies are the development of ligands with less peptide‐like character or the stabilization of a new and unexpected binding‐competent conformation of the protein through a novel ligand‐binding mode. Our rational design of pyrrolidinedimethylene diamines was inspired by the idea to incorporate key structural elements from classical peptidomimetics with a non‐peptidic heterocyclic core comprising an endocyclic amino function to address the catalytic aspartic acid side chains of Aspu200925 and 25′. The basic scaffolds were decorated by side chains already optimized for the recognition pockets of HIV protease or cathepsinu2005D. A multistep synthesis has been established to produce the central heterocycle and to give flexible access to side chain decorations. Depending on the substitution pattern of the pyrrolidine moiety, single‐digit micromolar inhibition of HIV‐1 protease and cathepsinu2005D has been achieved. Successful design is suggested in agreement with our modelling concepts. The subsequently determined crystal structure with HIV protease shows that the pyrrolidine moiety binds as expected to the pivotal position between both aspartic acid side chains. However, even though the inhibitors have been equipped symmetrically by polar acceptor groups to address the flap water molecule, it is repelled from the complex, and only one direct hydrogen bond is formed to the flap. A strong distortion of the flap region is detected, leading to a novel hydrogen bond which cross‐links the flap loops. Furthermore, the inhibitor addresses only three of the four available recognition pockets. It achieves only an incomplete desolvation compared with the similarly decorated amprenavir. Taking these considerations into account it is surprising that the produced pyrrolidine derivatives achieve micromolar inhibition and it suggests extraordinary potency of the new compound class. Most likely, the protonated pyrrolidine moiety experiences strong enthalpic interactions with the enzyme through the formation of two salt bridges to the aspartic acid side chains. This might provide challenging opportunities to combat resistance of the rapidly mutating virus.

Alpine drug discovery summit: 10th Swiss Course on Medicinal Chemistry.

Alpine fresh! Aimed at instructing young scientists at the beginning of their careers in industry, this medicinal chemistry course provides an overview of the state of the art techniques and current approaches to drug discovery and development.