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Using Synthetic Organic Chemistry: Chemical Biology to Create Small-molecule Probes of Biological Processes

Internationaliseringsstipendium | 02/05/2016

Multidisciplinary research in the 21st century is rich with opportunities and challenges. Particularly fruitful in this context is the interaction between chemistry and biology, where synthetic molecules are being used to systematically investigate the functions of genes, cells and biochemical pathways in living systems. Chemical biology is evolving at an unprecedented pace and holds a unique promise for fundamental discoveries within natural sciences in general. 

The proposed activities will give visibility to chemical biology and its role in life science research and provide the scientific community with a unique opportunity to gain knowledge in three distinct areas.  By mining the data from several screens against different targets, we can increase our understanding of complex biological systems. By identifying new targets for biological screening, we can formulate new strategies for the effective treatment of patients. By refining the hit compounds through follow-up chemistry, we can identify new tool compounds for biological research and acquire leads for drug discovery. Together, this will have a profound impact on research within chemical biology and will benefit the Danish research community and society through the generation of knowledge and innovation as well as by the training of highly skilled research personnel.


Chemical Biology

Chemical biology is a new and burgeoning interdisciplinary research field which has emerged from classical pharmacology and cell biology and is concerned with the study of the effects of chemical compounds on biological systems.1,2 In parallel, post-genome biology with its powerful technologies of genome sequencing, transcriptomics, proteomics and metabolomics has provided an exploding space of information on new cellular targets for basic research and early drug discovery. Success stories of the use of specifically designed chemical compounds that elicit a well defined biological effect (i.e. ‘tool’ compounds) highlighted the advantageous opportunities of these compounds for the modulation of functions of biological targets and for studying the underlying molecular mechanisms of cellular and organismal responses.3

Antibody–Drug Conjugates—A New Wave of Cancer Drugs

The discovery and development of new therapeutic agents has recently moved into a new key area, looking to combine two distinct classes of chemical or biological agents into a single entity. Bringing two different agents together provides the opportunity for synergistic effects, most notably when one of the components acts as a targeting agent and the other interacting with the desired biological system.4 One of the leading areas for new synergistic therapeutic modalities is Antibody Drug Conjugates (ADC)s.5-8

ADCs are comprised of three parts: a monoclonal antibody, a cytotoxic agent (the ‘warhead’) and a structural moiety that joins the two together (the ‘linker’). The antibody of an ADC is selected or engineered to bind to a tumour cell-specific antigen or to an antigen that is overexpressed on the surface of tumour cells. Thus, the antibody guides the ADC selectively to target tumour cells. Upon binding, the ADC is internalised and the cytotoxic agent is released from the antibody to perform its cell-killing function.5-8 ADCs hold considerable promise as anticancer agents, offering the potential of specific delivery of cytotoxic agents to tumour cells (targeted therapy), thereby avoiding the dose-limiting toxicity of chemotherapy that occurs as a result of its effects on normal cells.6

The present project looks to further develop two key related areas of ADC chemotherapeutics: (1) the selection and preparation of warheads and (2) the linker technology used. This will be the primary focus of the proposed research. The knowledge and insights gained could potentially be applied to other synergistic therapeutic modalities.

Relevance to Society and Industry

The proposed activities will contribute to meeting the 21th Century Grand Challenges set-out by the European Commission, including human health and ageing populations (e.g. new treatments and diagnostics) and food security (e.g. through plant protective agents). Chemical compounds are omnipresent in our daily lives as natural or synthetic products, be it the drugs to treat diseases, pesticides to protect crops, food additives, and many more. Therefore, both society and industry share a great interest in chemical biology. Groundbreaking insights into cellular and organismal metabolic or signaling pathways, which are involved, for example, in the progression of diseases, are gained by studying the effect of compounds on biological systems (pharmacology). This forms the basis for the development of novel diagnostic and therapeutic approaches in health research and also opens novel opportunities and benefits in many other areas of the life sciences. Chemical biology, with the tools and knowledge it generates, addresses all facets of the great societal challenges for healthy ageing, disease pandemics, food security etc. Taking into account that chronic diseases occupy a significant part of the health care spending, chemical biology research can show a significant socioeconomic gain.

What Motivates Me?

Following more than seven years of chemical research in academic institutions, I now have a strong in-depth knowledge of organic chemistry. Furthermore, the opportunity to do postdoctoral work in the distinguished group of Professor MacMillan, Princeton University, provided me not only with an outstanding knowledge of various organo- and organometal-catalysis methods, but also with international research experience and contacts, altogether factors of high significance for my career. My highly rewarding research stay in the MacMillan group9 was supported by a travel grant from the Carlsberg Foundation.

During my seven years of chemical research in academic institutions, I have had opportunities to work on a broad range of multidisciplinary chemistry projects, which include synthesis of new organic light-harvesting materials for energy-storage,10 development of site-selective peptide and protein labeling methodologies as well as various projects related to drug discovery (library design and generation, screening for biological activity and assay development).11 I have a high passion for chemistry projects that involve team workers/collaborators from a diverse range of backgrounds. By teaming up with complementary research groups one can combine the collective expertise and gain synergy. The challenges are substantial in multidisciplinary projects, and they continue to inspire me to perform the best. It is rewarding to conceive creative scientific ideas, to do the critical experiments, and feel the excitement when hypotheses are proven.

At this stage of my career, I hope to shape the foundation of my future research career in academia. I have a strong in-depth knowledge of organic chemistry and I am excited about the chance to expand my skill set and broaden my knowledge in the area of bioconjugation chemistry. The present project aims at developing novel Antibody-Drug Conjugates designed as a targeted therapy for the treatment of cancer and will be conducted in collaboration with Professor David Spring, Cambridge University. The prospects of working with Professor David Spring, a world-leading expert in chemical biology and bioconjugate synthesis, will provide me with experience and knowledge that will further strengthen my ability to lead and guide interdisciplinary chemical biology projects to coherent and impactful scientific discoveries.

References 

(1) Mitchison, T. J. Chem. Biol. 1994, 1, 3. 

(2) Stockwell, B. R. Nature Rev. Gent. 2010, 1, 116. 

(3) Mayer, T. U. et al. Sceince 1999, 286, 971. 

(4) Nicolaou, K. Angew. Chem. Int. Ed. 2014, 53, 9128. 

(5) Chari, R. V. J. et al. Angew. Chem. Int. Ed. 2014, 53, 3796. 

(6) Ducry, L.; Stump, B. Bioconjugate Chem. 2010, 21, 5. 

(7) Flygare, J. A. et al. Chem. Biol. Drug. Des. 2013, 81, 113. 

(8) Kitson, S. L. et al. ’Antibody-Drug Conjugates (ADCs) – Biotherapeutic bullets’ Chimica Oggi-Chemistry Today, July/August 2013, 31(4). 

(9) During my time in the MacMillan laboratory, I made significant contributions to the application of photoredox catalysis to the development of valuable new bond constructions by designing a new approach to C-H functionalization. These results were recently published in the highly prestigious journal ‘J. Am. Chem. Soc’:Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. J. Am Chem. Soc. 2014, 136, 626. 

(10) See for example: Qvortrup, K.; Bond, A. D.; Nielsen, A.; McKenzie, C. J.; Kilså, K.; Nielsen, M. B. Chem. Commun. 2008, 1986. (11) See for example: (a) Qvortrup, K.; Komnatnyy, V. V.; Nielsen, T. E. Org. Lett. 2014, 16, 4782. (b) Qvortrup, K.; Taveras, K. M.; Thastrup, O.; Nielsen, T. E. Chem. Commun. 2011, 47, 1309.