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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.
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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
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