Drug Discovery Today: Technologies
Vol. 10, No. 4 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Small-molecule modulation of protein–protein interactions
Small-molecule modulation of protein–protein interactions Christian Ottmann Department of Biomedical Engineering, Technische Universiteit Eindhoven, P.O. Box 513, 5600 MB Eindhoven, The Netherlands. Email: ([email protected])
With an estimated number between 130,000 and 650,000 protein–protein interactions (PPIs) in human biology represent a tremendous potential for drug discovery. Furthermore, a number of natural products like brefeldin A and forskolin as well as approved drugs (rapamycin, FK506) targeting specific PPIs prove that addressing this huge interactome with small, drug-like molecules is a feasible strategy. However, this situation should not conceal that the technological demands of drug discovery in the field of PPI modulation are still formidable. Starting from the initial identification of candidate molecules via Highthroughput-Screening, the clear biophysical evaluation of their mode-of-action and – most importantly – their optimization via chemical synthesis, many obstacles that due to decade-long experience and a wealth of success stories are more or less ‘routine’ in other fields, are still very difficult for PPIs. While the community awaits the first approvals from a dedicated PPI inhibition approach (e.g. Navitoclax, disrupting the BclXL/Bak interaction, or RG117 – a Nutlin derivative – inhibiting the binding of Mdm2 to p53), a considerably growing number of proof-of-principle and advanced compound development papers appeared in the past 1–2 years. Hence, small-molecule modulation of PPIs finally seems to enter a mature state, consolidating this approach as a major pillar for the development of novel and innovative drugs. This issue of ‘Drug Discovery Today: Technologies’ comprises a number of reports of modulators of medically highly relevant PPIs. The first article by Christopher Wilson and Michelle Arkin reviews the successful use of Tethering as a fragment-screening method to probe the structural adaptivity at PPI interfaces. This method takes advantage of thiolatedisulfide exchange to trap fragments bound to a protein surface and helped for example researchers at Sunesis to develop an nM-inhibitor of the IL2/IL2R interaction. In a contribution by Laura Silvian and colleagues the consequences for drug discovery resulting from the features 1740-6749/$ ß 2013 Elsevier Ltd. All rights reserved.
and peculiarities of PPI interfaces are picked up and recent improvements in different technological fields to tackle the problem of chemically addressing these interfaces are discussed. These include protein crystallography, in-silico drug design, biophysical screening and medicinal chemistry that all help to enable drug discovery on PPIs without principally changing the fact that therapeutic PPI intervention remains as one of the most challenging endeavors of our industry. In the third review, Zeger Debyser and colleagues sum up the successes in developing inhibitors of the interaction between HIV integrase (IN) and its human host co-factor LEDGF (Lens epithelium-derived growth factor). HIV depends for efficient replication on the IN/LEDGF interaction and disruption of this PPI by the so-called LEDGINs promises to lead to an innovative new approach in HIV therapy. In addition to enzymes like IN, the HIV genome also encodes four accessory factors – Vpr, Vpu, Vif and Nef – that Christian Ottmann, Ph.D., is Associate Professor for Molecular Cell and Structural Biology at Eindhoven University of Technology, The Netherlands. He works on small-molecule modulation of Protein–Protein Interactions (PPIs) with a special focus on stabilization of 14-3-3 adapter protein PPIs. He is involved in several early drug discovery projects with the pharmaceutical industry and is coordinator of the FP7 IndustryAcademia Partnership and Pathways (IAPP) 14-3-3STABS. Before taking up his current position in Eindhoven he was a group leader at the Chemical Genomics Centre (CGC) of the Max Planck Society in Dortmund, Germany. He obtained his Ph.D. (summa cum laude) in 2003 from the University of Tu¨bingen with Prof. Claudia Oecking. In 2012 he was recipient of the Innovation Award in Medicinal/Pharmaceutical Chemistry of the GDCh/DPhG. He is (co-) author of more than 50 scientific papers and 3 patents.
http://dx.doi.org/10.1016/j.ddtec.2013.08.001
e499
Drug Discovery Today: Technologies | Small-molecule modulation of protein–protein interactions
are also essential for viral pathogenicity. HIV-Nef for example displays no enzyme activity but relies solely on protein– protein interactions to convey its physiological effects. Thomas Smithgall and Gary Thomas review examples of small molecule antagonists of HIV Nef function targeting Nef interaction with SH3 domains, or Src family kinases like Lyn, c-Src and Hck. Matthieu Sainlos and colleagues review the different approaches to inhibit PPIs mediated by PDZ domains. These interaction modules are found in more than 150 human proteins, for example the chloride channel CFTR, the protease Htra1 or the protein kinase LIMK1 and are hence involved in a number of physiological processes. PDZ domains bind short, linear peptide motifs in the C-termini of the partner proteins with low-mM affinities and the respective motives are generally able to interact with a multitude of PDZ domains. The consequences for the design of inhibitors – that is stronger focus on specificity compared to high affinity – are discussed by the authors in light of the different molecular approaches (small molecules, peptidomimetics among others).
e500
www.drugdiscoverytoday.com
Vol. 10, No. 4 2013
Finally, Maurizio Botta and colleagues summarize the current state of small-molecule modulation of PPIs involving the adapter class of 14-3-3 proteins. These proteins interact with several hundred partner proteins and influence a plethora of physiological processes, many of them involved in human diseases like cancer, neurodegeneration, obesity and inflammation. Complementary to PPI inhibition, 14-3-3 PPIs are also excellent examples for the opposite strategy, small-molecule PPI stabilization. Here, Botta et al. review a number of natural products and compounds resulting from HTS that confer their activity by acting as ‘molecular glues’ of certain 14-3-3 PPIs. Taken together, this special issue of ‘Drug Discovery Today: Technologies’ provides a nice collection of reviews covering some of the ever-growing number of important PPIs that nowadays are amenable to the drug development process. With best wishes,
Christian Ottmann
Vol. 10, No. 4 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Small-molecule modulation of protein–protein interactions
Small-molecule modulation of protein–protein interactions Christian Ottmann Department of Biomedical Engineering, Technische Universiteit Eindhoven, P.O. Box 513, 5600 MB Eindhoven, The Netherlands. Email: ([email protected])
With an estimated number between 130,000 and 650,000 protein–protein interactions (PPIs) in human biology represent a tremendous potential for drug discovery. Furthermore, a number of natural products like brefeldin A and forskolin as well as approved drugs (rapamycin, FK506) targeting specific PPIs prove that addressing this huge interactome with small, drug-like molecules is a feasible strategy. However, this situation should not conceal that the technological demands of drug discovery in the field of PPI modulation are still formidable. Starting from the initial identification of candidate molecules via Highthroughput-Screening, the clear biophysical evaluation of their mode-of-action and – most importantly – their optimization via chemical synthesis, many obstacles that due to decade-long experience and a wealth of success stories are more or less ‘routine’ in other fields, are still very difficult for PPIs. While the community awaits the first approvals from a dedicated PPI inhibition approach (e.g. Navitoclax, disrupting the BclXL/Bak interaction, or RG117 – a Nutlin derivative – inhibiting the binding of Mdm2 to p53), a considerably growing number of proof-of-principle and advanced compound development papers appeared in the past 1–2 years. Hence, small-molecule modulation of PPIs finally seems to enter a mature state, consolidating this approach as a major pillar for the development of novel and innovative drugs. This issue of ‘Drug Discovery Today: Technologies’ comprises a number of reports of modulators of medically highly relevant PPIs. The first article by Christopher Wilson and Michelle Arkin reviews the successful use of Tethering as a fragment-screening method to probe the structural adaptivity at PPI interfaces. This method takes advantage of thiolatedisulfide exchange to trap fragments bound to a protein surface and helped for example researchers at Sunesis to develop an nM-inhibitor of the IL2/IL2R interaction. In a contribution by Laura Silvian and colleagues the consequences for drug discovery resulting from the features 1740-6749/$ ß 2013 Elsevier Ltd. All rights reserved.
and peculiarities of PPI interfaces are picked up and recent improvements in different technological fields to tackle the problem of chemically addressing these interfaces are discussed. These include protein crystallography, in-silico drug design, biophysical screening and medicinal chemistry that all help to enable drug discovery on PPIs without principally changing the fact that therapeutic PPI intervention remains as one of the most challenging endeavors of our industry. In the third review, Zeger Debyser and colleagues sum up the successes in developing inhibitors of the interaction between HIV integrase (IN) and its human host co-factor LEDGF (Lens epithelium-derived growth factor). HIV depends for efficient replication on the IN/LEDGF interaction and disruption of this PPI by the so-called LEDGINs promises to lead to an innovative new approach in HIV therapy. In addition to enzymes like IN, the HIV genome also encodes four accessory factors – Vpr, Vpu, Vif and Nef – that Christian Ottmann, Ph.D., is Associate Professor for Molecular Cell and Structural Biology at Eindhoven University of Technology, The Netherlands. He works on small-molecule modulation of Protein–Protein Interactions (PPIs) with a special focus on stabilization of 14-3-3 adapter protein PPIs. He is involved in several early drug discovery projects with the pharmaceutical industry and is coordinator of the FP7 IndustryAcademia Partnership and Pathways (IAPP) 14-3-3STABS. Before taking up his current position in Eindhoven he was a group leader at the Chemical Genomics Centre (CGC) of the Max Planck Society in Dortmund, Germany. He obtained his Ph.D. (summa cum laude) in 2003 from the University of Tu¨bingen with Prof. Claudia Oecking. In 2012 he was recipient of the Innovation Award in Medicinal/Pharmaceutical Chemistry of the GDCh/DPhG. He is (co-) author of more than 50 scientific papers and 3 patents.
http://dx.doi.org/10.1016/j.ddtec.2013.08.001
e499
Drug Discovery Today: Technologies | Small-molecule modulation of protein–protein interactions
are also essential for viral pathogenicity. HIV-Nef for example displays no enzyme activity but relies solely on protein– protein interactions to convey its physiological effects. Thomas Smithgall and Gary Thomas review examples of small molecule antagonists of HIV Nef function targeting Nef interaction with SH3 domains, or Src family kinases like Lyn, c-Src and Hck. Matthieu Sainlos and colleagues review the different approaches to inhibit PPIs mediated by PDZ domains. These interaction modules are found in more than 150 human proteins, for example the chloride channel CFTR, the protease Htra1 or the protein kinase LIMK1 and are hence involved in a number of physiological processes. PDZ domains bind short, linear peptide motifs in the C-termini of the partner proteins with low-mM affinities and the respective motives are generally able to interact with a multitude of PDZ domains. The consequences for the design of inhibitors – that is stronger focus on specificity compared to high affinity – are discussed by the authors in light of the different molecular approaches (small molecules, peptidomimetics among others).
e500
www.drugdiscoverytoday.com
Vol. 10, No. 4 2013
Finally, Maurizio Botta and colleagues summarize the current state of small-molecule modulation of PPIs involving the adapter class of 14-3-3 proteins. These proteins interact with several hundred partner proteins and influence a plethora of physiological processes, many of them involved in human diseases like cancer, neurodegeneration, obesity and inflammation. Complementary to PPI inhibition, 14-3-3 PPIs are also excellent examples for the opposite strategy, small-molecule PPI stabilization. Here, Botta et al. review a number of natural products and compounds resulting from HTS that confer their activity by acting as ‘molecular glues’ of certain 14-3-3 PPIs. Taken together, this special issue of ‘Drug Discovery Today: Technologies’ provides a nice collection of reviews covering some of the ever-growing number of important PPIs that nowadays are amenable to the drug development process. With best wishes,
Christian Ottmann
