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  Areas of Excellence Scheme Project: Achievement Summary of The Institute
of Molecular Technology for Drug Discovery and Synthesis

  Areas of Excellence Scheme Project: Molecular Neuroscience: Basic
Research and Drug Discovery

The Institute of Molecular Technology for Drug Discovery and Synthesis (IMT) is established under the Areas of Excellence (AoE) Scheme administered by the University Grants Committee (UGC) of the Hong Kong Special Administrative Region. IMT has led Hong Kong to become a leading research center for drug discovery and synthesis by the following means:

Identification of anticancer metal-based drug leads
Through this project, Hong Kong has become a center with international reputation in research on Metal Based Drugs. Libraries of bioactive compounds of gold, ruthenium, platinum and rhodium with promising anticancer activities have been created. In particular, the anticancer gold compounds gold-1a, gold-2a and gold-3d identified in this project show exceptionally good in vivo activities for killing drug resistant cancer cells and with much higher potencies than the clinically-used cisplatin. Gold-2a shows significant inhibition to tumor growth of breast cancer in vivo with no apparent toxic side effect. Gold-3d shows anticancer property toward hepatocellular and nasopharyngeal carcinoma in nude mice and rat models. Pre
-clinical safety pharmacological evaluations, including acute toxicity and genotoxicity studies on gold-3d, have revealed promising results. Potential molecular targets of these gold drug leads, including topoisomerases, proteasome, deubiquitinating enzymes, HDAC, Bcl-2, Wnt, TrxR and Fas, were identified by a combination of computational, transcriptomics and proteomics techniques. The international pharmaceutical companies Servier (France) and Goldebv Biotech (Taiwan) have agreed to co-develop or have provided sponsorships to develop these drug leads. Three patents have been granted by the US Patent and Trademark Office and one patent has been granted by Taiwan Intellectual Property Office on Metals in Medicines. The Inorganic Medicines has drawn substantial attention from and stimulated active researches in various tertiary institutions to develop this research field in Hong Kong.

Chemistry and biology of natural product drug candidates
Natural products targeting at TNF-α have been identified by high-throughput virtual screening via molecular docking and validated by biochemical experiments. Bioactive saponins extracted from herbs show cytotoxicity against cancer cells. Proteomic and cellular studies revealed that these bioactive saponins trigger apoptosis through mitochondrial pathways. Timosaponin AIII is a pronounced activator of autophagy. Novel alkaloid-based compounds (cantharimide and phthalimide) and their chiral derivatives were found to exhibit in vitro cytotoxic effects on human cancer cell lines. Collaboration with Eli Lilly (a global pharmaceutical company) has been set up for the development of these lead compounds as novel anticancer agents. One US patent on osteoblastogenesis agents has been granted. The total synthesis of several bioactive natural compounds, including pseudolaric acids, (±)-pallavicinolide and diastereomers of plakortone B, have been accomplished.

Biosensing and molecular imaging technologies based on novel luminescent organic and inorganic compounds
Phosphorescent metal complexes have been developed for imaging of biological thiols, proteins and DNA in cells with high selectivity and sensitivity. Notable examples include luminescent platinum(II) complexes for sensitive and specific in-gel detection of TopoI-DNA complexes, G-quadruplex DNA specific luminescent probes, and luminescent switch-on probes based on cyclometalated platinum(II) and cyclometalated iridium(III) complexes for detection of proteins down to 1.5 ng. Innovative fluorescent beta-lactamase biosensor has been developed for rapid and sensitive screening of antibiotics. One US patent on the beta-lactamase biosensor has been granted. An imaging mass spectrometry platform for the analysis of intact biological tissues has been established. This platform has been used to image the distribution of metabolites in animal tissues, and phytochemicals in herbal tissues.

Advanced synthetic methods
A panel of novel and efficient metal catalyzed organic reactions for highly efficient chemical synthesis with diversity, including rutheniumbased, gold-based, iron-based and palladium
-based catalysis, have been developed. In addition, enantioselective aldol-type reaction was successfully applied to the preparation of Ostemivir (Tamiflu) scaffold. Two US patents on “Diastereoselective Epoxidation of Allylically Substituted Alkenes Using Metalloporphyrin Catalysts” and “Ligand for Transition Metals and Their Method of Uses” have been granted. Green Oxidation using air or hydrogen peroxide as terminal oxidant, and using the biocompatible and inexpensive iron catalysts, have been developed for various organic transformation reactions, including hydroxylation of alkanes, epoxidation of alkenes, demethylation of tertiary amines and oxidative C–C bond cross-coupling reaction of tertiary amines. These catalytic reactions invented in this project allow the creation of libraries of bioactive organic compounds unique to Hong Kong for research on drug discovery.
Comprehensive infrastructures and facilities for drug discovery and synthesis in Hong Kong
Chemical libraries of bioactive compounds unique to Hong Kong have been created with their structures modified efficiently for drug discovery research. Two State Key Laboratories, the State Key Laboratory of Synthetic Chemistry and the State Key Laboratory of Chirosciences have been established in Hong Kong to support the long term development of Synthetic Chemistry for drug research. The University of Hong Kong has allocated an additional laboratory space of 600 m2 for Drug Discovery and Chemical Biology research activities in the newly built Human Research Institute. Computer-aided drug design platform has been established to facilitate high-throughput virtual screening of drug candidates and to optimize the effectiveness of drug candidate binding to molecular targets in a cost-effective and efficient manner. High throughput screening systems, including multi-mode microplate workstations, high field 600MHz magnetic resonance spectrometer and high performance tandem mass spectrometry facility, have been established to support the research on Chemical Biology. A number of young scientists with complementary expertise from Chemical Synthesis to Chemical Biology, Molecular Biology, Phytochemistry, and Bioinformatics have been nurtured. They are working as faculty members in various Universities in Hong Kong and in tertiary institutions in neighboring regions, such as Jinan University in China, Nanyang Technological University in Singapore, and University of Macau. This group of young scientists with the same vision in research would excel in their own fields as well as to contribute to pushing the research frontier on drug discovery and synthesis in Hong Kong in the forthcoming decades.

Introducing the work and achievement of IMT, Prof Chi-Ming Che gave a public lecture on “Chemical Biology: Anti-Cancer Gold Drugs and Traditional Chinese Medicine” organised by the RGC and Hong Kong Science Museum.

International recognition of research achievements
In the period of 2001-2011, a total of 724 research articles with citations of over 10,000 times covering chemical synthesis, inorganic medicines, natural compounds, biosensing and molecular imaging technology, have been published in international peer-reviewed journals, including Accounts of Chemical Research, Angewandte Chemie International Edition, Chemical Society Reviews, Journal of the American Chemical Society, Journal of the National Cancer Institute, Proceedings of the National Academy of Sciences of the United States of America. In addition, members of the IMT have received prestigious awards: including Edward Clark Lee Lectureship at the University of Chicago, Seaborg Lectureship at University of California, Berkeley, Keynote Lecture in Dalton Discussion 10: Applications of Metals in Medicine and Healthcare (Durham), 1st Class National Science Award of China, TWAS Prize in Chemistry, Pfizer Lectureship, Gold Medal in the Fifth China International Invention Expo, Federation of Asian Chemical Societies (FACS) Foundation Lectureship Award, and Croucher Senior Research Fellowship. Members of IMT have been invited to serve as editorial board members of various international journals. The research achievements have also attracted more than HK$75 millions additional research grants including special equipment grants, group collaborative research grants, as well as innovative and technology fund.

Impact to the future drug research in Hong Kong
The IMT is the first of its kind in joining the efforts of various local universities to a research theme. The project successfully enhances inter
-institutional and inter-disciplinary collaboration and knowledge exchange for drug research among the local universities. Collaborations have been established with renowned institutions. The research infrastructure and personnel for drug research established from the IMT program continue to push the future drug development in Hong Kong. The further development of identified drug leads can help to boost the development of biotechnology and pharmaceutical industry in Hong Kong in the forthcoming decades. Indeed, an international renowned pharmaceutical company has signed contract agreement to fully finance the development of a new drug based on the research finding in this project.

Project Coordinator:
Prof Chi-Ming CHE
The University of Hong Kong