European Journal of Medicinal Chemistry 88 (2014) 1e2
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech
Editorial
Chemical biology & drug discovery
Chemical biology continues to significantly impact therapeutic research. This special issue in EJMC nicely highlights the synergy between chemical biology and medicinal chemistry, as applied in the drug discovery setting. The impressive breadth of research covered in the issue demonstrates the wide variety of opportunities for chemical biology to influence the direction of drug discovery. Areas featured in the issue include chemistry-enabled/enhanced biotherapeutics (or chemologics), nanotechnology, molecular pharmacology, chemoproteomics and imaging probe development. Molecular design and synthesis underpin the medicinal chemistry discipline, although most of the focus in this area has been towards the development of small molecule therapeutics. Chemologics research harnesses the expertise in small molecule design and synthesis to enhance or enable biologicals, where a certain amount of empiricism has traditionally driven therapeutic development [1,2]. Antibody-drug conjugates (ADCs) bring small and large molecule approaches into one modality, specifically through antibody-mediated targeting of small molecule therapeutic payloads to desired cells and tissues. Rabuka and co-workers [4] have explored the effects of linker architecture on site-specific antibody conjugates for the first time using an aldehyde-hydrazino-iso-Pictet-Spengler (HIPS) ligation. This work showed that the choice of linker between the maytansine payload and the directing antibody impacted the biophysical and functional properties of the resulting ADCs. Cellular delivery of peptides is a challenging issue for therapeutic development in this space. Craik and co-workers [5] developed interesting SAR for two cell-penetrating disulfide-rich cyclic peptides (MCoTI-II and SFTI-1) that explored the impact of sequence changes in cellular uptake experiments. This work will no doubt translate to other areas of peptide delivery research. Bisht and co-workers [6] evaluate the antibacterial activity of novel ornithine-based lipopeptides against antibiotic-resistant clinical isolates. Electron microscopy and calcein dye leakage experiments confirmed the membranolytic effects of these interesting molecules, which were also shown to be stable in human plasma. Importantly, clinical isolates exhibited no signs of resistance development to the lipopeptides. New technologies are essential to understand biology and in particular, to help delineate the mode of action and molecular pharmacology of novel therapeutic agents. Garcia and Carroll [7] developed a sensitive technique to measure oxidized protein tyrosine phosphatases (PTPs) using redox-based chemical probes in cellular contexts. These probes also provide opportunities for the development of phosphatase inhibitors that nucleophilically attack the oxidized catalytic cysteine observed in pathophysiologicallyrelevant conditions. Correa and co-workers [8] used a SNAP-tag based selective crosslinking approach (S-CROSS) to investigate http://dx.doi.org/10.1016/j.ejmech.2014.10.017 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.
the homodimer formation of the epidermal growth factor receptor (EGFR). Using this approach the authors showed that EGFR forms constitutive transient receptorereceptor interactions in unstimulated cells and that the effects of small molecules on this signaling could be interrogated. Nanopore technologies have shown considerable utility in drug discovery from DNA sequencing to proteomics. Lee and co-workers [9] used nanopore analysis to evaluate the binding of natural products to a-synuclein, a misfolded protein that forms fibrils in the Lewy bodies associated with Parkinson's disease (PD). Nicotine and caffeine were found to bind to a-synuclein and may provide new leads for the treatment of PD. Amyloid fibrils possess unique material properties and provide new opportunities for the development of bionanomaterials. Rijkers and co-workers [10] describe the design and synthesis of N-terminally functionalized Ab(16e22) peptides that underwent pH-mediated polymorphism to peptide tapes and nanotubes. This work holds considerable promise for the creation of nanowires and biodegradable materials. Molecular imaging approaches have found considerable utility in drug discovery and development, although improved technologies are urgently required to advance the field. Tonge and coworkers [11] used positron emission tomography (PET) imaging to determine the biodistribution and pharmacokinetics in mice of a Staphylococcus aureus enoyl-ACP reductase inhibitor. The 11Clabeled PET probe provided useful information to enable PKPD modeling with a view to imaging bacterial infection in vivo. Morris and co-workers [12] review the development and application of cyclin-dependent kinase (CDK) fluorescent biosensors that report on CDK activity both in vitro and in vivo. This work also led to the creation of novel screening technologies for the identification of new classes of CDK inhibitors. Chemical probes provide a powerful means to validate new € hn and co-workers [13] therapeutically relevant targets [3]. Ko describe the application of virtual screening to identify novel inhibitors of the cancer-related phosphatases of regenerating liver (PRL) family. SAR optimization led to a PRL inhibitor that can be used to further explore the therapeutic potential of inhibiting the PRL proteins. Moreover, the lead molecule was found to be fluorescent and therefore provides opportunities for fluorescence microscopy imaging. Smelcerovic and co-workers [14] nicely review the area of DNase inhibition and highlight the need for further selective probes to understand the biochemistry of this class. Finally, we thank the contributors to this special issue. Their expertise and innovations at the chemical biology-drug discovery interface have emphasized the considerable opportunities in this space.
2
Editorial / European Journal of Medicinal Chemistry 88 (2014) 1e2
References [1] L.H. Jones, Chemologics, in: M.E. Bunnage (Ed.), New Frontiers in Chemical Biology, RSC Publishing, Cambridge UK, 2011. [2] L.H. Jones, A.J. McKnight, Biotherapeutics: Recent Developments Using Chemical and Molecular Biology, RSC Publishing, Cambridge UK, 2013. [3] M.E. Bunnage, E.L.P. Chekler, L.H. Jones, Target validation using chemical probes, Nat. Chem. Biol. 9 (2013) 195e199. [4] A.E. Albers, A.W. Garofalo, P.M. Drake, R. Kudirka, G.W. de Hart, R.M. Barfield, J. Baker, S. Banas, D. Rabuka, Exploring the effects of linker composition on site-specifically modified antibodyedrug conjugates, Eur. J. Med. Chem. 88 (2014) 3e9. [5] C. D'Souza, S.T. Henriques, C.K. Wang, D.J. Craik, Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1, Eur. J. Med. Chem. 88 (2014) 10e18. [6] S. Lohan, J. Monga, S.S. Cameotra, G.S. Bisht, In vitro and in vivo antibacterial evaluation and mechanistic study of ornithine based small cationic lipopeptides against antibiotic resistant clinical isolates, Eur. J. Med. Chem. 88 (2014) 19e27. [7] F.J. Garcia, K.S. Carroll, Redox-based probes as tools to monitor oxidized protein tyrosine phosphatases in living cells, Eur. J. Med. Chem. 88 (2014) 28e33. [8] C.L. Varela, C. Amaral, E.T. da Silva, A. Lopes, G. Correia-da-Silva, R.A. Carvalho, S.C.P. Costa, F.M.F. Roleira, N. Teixeira, Exemestane metabolites: synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line, Eur. J. Med. Chem. 87 (2014) 336e345. [9] O. Tavassoly, J. Kakish, S. Nokhrin, O. Dmitriev, J.S. Lee, The use of nanopore analysis for discovering drugs which bind to a-synuclein for treatment of Parkinson's disease, Eur. J. Med. Chem. 88 (2014) 42e54. [10] R.C. Elgersma, L.M.J. Kroon-Batenburg, G. Posthuma, J.D. Meeldijk, D.T.S. Rijkers, R.M.J. Liskamp, pH-controlled aggregation polymorphism of amyloidogenic Ab(16e22): Insights for obtaining peptide tapes and peptide
[11]
[12]
[13]
[14]
nanotubes, as function of the N-terminal capping moiety, Eur. J. Med. Chem. 88 (2014) 55e65. H. Wang, Y. Lu, L. Liu, S.W. Kim, J.M. Hooker, J.S. Fowler, P.J. Tonge, Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus, Eur. J. Med. Chem. 88 (2014) 66e73. vel, L. Kurzawa, T.N. Ngoc Van, M.C. Morris, Fluorescent biosensors for C. Pre drug discovery new tools for old targets - screening for inhibitors of cyclindependent kinases, Eur. J. Med. Chem. 88 (2014) 74e88. € hn, Biochemical evaluation of virtual B. Hoeger, M. Diether, P.J. Ballester, M. Ko screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver, Eur. J. Med. Chem. 88 (2014) 89e100. A. Kolarevic, D. Yancheva, G. Kocic, A. Smelcerovic, Deoxyribonuclease inhibitors, Eur. J. Med. Chem. 88 (2014) 101e111.
Lyn H. Jones, Dr.* Worldwide Medicinal Chemistry, Pfizer BioTherapeutics Chemistry, Cambridge, MA, USA Christian Heinis, Professor Laboratory of Therapeutic Proteins and Peptides (LPPT), Ecole ^ Polytechnique Federale de Lausanne (EPFL), BCH 5305 (Batochime), Lausanne CH-1015, Switzerland E-mail address: christian.heinis@epfl.ch. * Corresponding author. E-mail address: Lyn.Jones@pfizer.com (L.H. Jones).
Available online 8 October 2014
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech
Editorial
Chemical biology & drug discovery
Chemical biology continues to significantly impact therapeutic research. This special issue in EJMC nicely highlights the synergy between chemical biology and medicinal chemistry, as applied in the drug discovery setting. The impressive breadth of research covered in the issue demonstrates the wide variety of opportunities for chemical biology to influence the direction of drug discovery. Areas featured in the issue include chemistry-enabled/enhanced biotherapeutics (or chemologics), nanotechnology, molecular pharmacology, chemoproteomics and imaging probe development. Molecular design and synthesis underpin the medicinal chemistry discipline, although most of the focus in this area has been towards the development of small molecule therapeutics. Chemologics research harnesses the expertise in small molecule design and synthesis to enhance or enable biologicals, where a certain amount of empiricism has traditionally driven therapeutic development [1,2]. Antibody-drug conjugates (ADCs) bring small and large molecule approaches into one modality, specifically through antibody-mediated targeting of small molecule therapeutic payloads to desired cells and tissues. Rabuka and co-workers [4] have explored the effects of linker architecture on site-specific antibody conjugates for the first time using an aldehyde-hydrazino-iso-Pictet-Spengler (HIPS) ligation. This work showed that the choice of linker between the maytansine payload and the directing antibody impacted the biophysical and functional properties of the resulting ADCs. Cellular delivery of peptides is a challenging issue for therapeutic development in this space. Craik and co-workers [5] developed interesting SAR for two cell-penetrating disulfide-rich cyclic peptides (MCoTI-II and SFTI-1) that explored the impact of sequence changes in cellular uptake experiments. This work will no doubt translate to other areas of peptide delivery research. Bisht and co-workers [6] evaluate the antibacterial activity of novel ornithine-based lipopeptides against antibiotic-resistant clinical isolates. Electron microscopy and calcein dye leakage experiments confirmed the membranolytic effects of these interesting molecules, which were also shown to be stable in human plasma. Importantly, clinical isolates exhibited no signs of resistance development to the lipopeptides. New technologies are essential to understand biology and in particular, to help delineate the mode of action and molecular pharmacology of novel therapeutic agents. Garcia and Carroll [7] developed a sensitive technique to measure oxidized protein tyrosine phosphatases (PTPs) using redox-based chemical probes in cellular contexts. These probes also provide opportunities for the development of phosphatase inhibitors that nucleophilically attack the oxidized catalytic cysteine observed in pathophysiologicallyrelevant conditions. Correa and co-workers [8] used a SNAP-tag based selective crosslinking approach (S-CROSS) to investigate http://dx.doi.org/10.1016/j.ejmech.2014.10.017 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.
the homodimer formation of the epidermal growth factor receptor (EGFR). Using this approach the authors showed that EGFR forms constitutive transient receptorereceptor interactions in unstimulated cells and that the effects of small molecules on this signaling could be interrogated. Nanopore technologies have shown considerable utility in drug discovery from DNA sequencing to proteomics. Lee and co-workers [9] used nanopore analysis to evaluate the binding of natural products to a-synuclein, a misfolded protein that forms fibrils in the Lewy bodies associated with Parkinson's disease (PD). Nicotine and caffeine were found to bind to a-synuclein and may provide new leads for the treatment of PD. Amyloid fibrils possess unique material properties and provide new opportunities for the development of bionanomaterials. Rijkers and co-workers [10] describe the design and synthesis of N-terminally functionalized Ab(16e22) peptides that underwent pH-mediated polymorphism to peptide tapes and nanotubes. This work holds considerable promise for the creation of nanowires and biodegradable materials. Molecular imaging approaches have found considerable utility in drug discovery and development, although improved technologies are urgently required to advance the field. Tonge and coworkers [11] used positron emission tomography (PET) imaging to determine the biodistribution and pharmacokinetics in mice of a Staphylococcus aureus enoyl-ACP reductase inhibitor. The 11Clabeled PET probe provided useful information to enable PKPD modeling with a view to imaging bacterial infection in vivo. Morris and co-workers [12] review the development and application of cyclin-dependent kinase (CDK) fluorescent biosensors that report on CDK activity both in vitro and in vivo. This work also led to the creation of novel screening technologies for the identification of new classes of CDK inhibitors. Chemical probes provide a powerful means to validate new € hn and co-workers [13] therapeutically relevant targets [3]. Ko describe the application of virtual screening to identify novel inhibitors of the cancer-related phosphatases of regenerating liver (PRL) family. SAR optimization led to a PRL inhibitor that can be used to further explore the therapeutic potential of inhibiting the PRL proteins. Moreover, the lead molecule was found to be fluorescent and therefore provides opportunities for fluorescence microscopy imaging. Smelcerovic and co-workers [14] nicely review the area of DNase inhibition and highlight the need for further selective probes to understand the biochemistry of this class. Finally, we thank the contributors to this special issue. Their expertise and innovations at the chemical biology-drug discovery interface have emphasized the considerable opportunities in this space.
2
Editorial / European Journal of Medicinal Chemistry 88 (2014) 1e2
References [1] L.H. Jones, Chemologics, in: M.E. Bunnage (Ed.), New Frontiers in Chemical Biology, RSC Publishing, Cambridge UK, 2011. [2] L.H. Jones, A.J. McKnight, Biotherapeutics: Recent Developments Using Chemical and Molecular Biology, RSC Publishing, Cambridge UK, 2013. [3] M.E. Bunnage, E.L.P. Chekler, L.H. Jones, Target validation using chemical probes, Nat. Chem. Biol. 9 (2013) 195e199. [4] A.E. Albers, A.W. Garofalo, P.M. Drake, R. Kudirka, G.W. de Hart, R.M. Barfield, J. Baker, S. Banas, D. Rabuka, Exploring the effects of linker composition on site-specifically modified antibodyedrug conjugates, Eur. J. Med. Chem. 88 (2014) 3e9. [5] C. D'Souza, S.T. Henriques, C.K. Wang, D.J. Craik, Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1, Eur. J. Med. Chem. 88 (2014) 10e18. [6] S. Lohan, J. Monga, S.S. Cameotra, G.S. Bisht, In vitro and in vivo antibacterial evaluation and mechanistic study of ornithine based small cationic lipopeptides against antibiotic resistant clinical isolates, Eur. J. Med. Chem. 88 (2014) 19e27. [7] F.J. Garcia, K.S. Carroll, Redox-based probes as tools to monitor oxidized protein tyrosine phosphatases in living cells, Eur. J. Med. Chem. 88 (2014) 28e33. [8] C.L. Varela, C. Amaral, E.T. da Silva, A. Lopes, G. Correia-da-Silva, R.A. Carvalho, S.C.P. Costa, F.M.F. Roleira, N. Teixeira, Exemestane metabolites: synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line, Eur. J. Med. Chem. 87 (2014) 336e345. [9] O. Tavassoly, J. Kakish, S. Nokhrin, O. Dmitriev, J.S. Lee, The use of nanopore analysis for discovering drugs which bind to a-synuclein for treatment of Parkinson's disease, Eur. J. Med. Chem. 88 (2014) 42e54. [10] R.C. Elgersma, L.M.J. Kroon-Batenburg, G. Posthuma, J.D. Meeldijk, D.T.S. Rijkers, R.M.J. Liskamp, pH-controlled aggregation polymorphism of amyloidogenic Ab(16e22): Insights for obtaining peptide tapes and peptide
[11]
[12]
[13]
[14]
nanotubes, as function of the N-terminal capping moiety, Eur. J. Med. Chem. 88 (2014) 55e65. H. Wang, Y. Lu, L. Liu, S.W. Kim, J.M. Hooker, J.S. Fowler, P.J. Tonge, Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus, Eur. J. Med. Chem. 88 (2014) 66e73. vel, L. Kurzawa, T.N. Ngoc Van, M.C. Morris, Fluorescent biosensors for C. Pre drug discovery new tools for old targets - screening for inhibitors of cyclindependent kinases, Eur. J. Med. Chem. 88 (2014) 74e88. € hn, Biochemical evaluation of virtual B. Hoeger, M. Diether, P.J. Ballester, M. Ko screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver, Eur. J. Med. Chem. 88 (2014) 89e100. A. Kolarevic, D. Yancheva, G. Kocic, A. Smelcerovic, Deoxyribonuclease inhibitors, Eur. J. Med. Chem. 88 (2014) 101e111.
Lyn H. Jones, Dr.* Worldwide Medicinal Chemistry, Pfizer BioTherapeutics Chemistry, Cambridge, MA, USA Christian Heinis, Professor Laboratory of Therapeutic Proteins and Peptides (LPPT), Ecole ^ Polytechnique Federale de Lausanne (EPFL), BCH 5305 (Batochime), Lausanne CH-1015, Switzerland E-mail address: christian.heinis@epfl.ch. * Corresponding author. E-mail address: Lyn.Jones@pfizer.com (L.H. Jones).
Available online 8 October 2014
