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Professor CHAI Li Lin, Christina

BSc (Chemistry) Hons (University of Canterbury, NZ)
PhD (Australian National University, Australia)
Post-Doc (Oxford University, UK)

Department of Pharmacy, National University of Singapore
18 Science Drive 4, Singapore 117543
Tel: +65 6601 1061
Fax: +65 6779 1554
Email: phacllc@nus.edu.sg

Biography

 

Prof Christina Chai obtained her BSc (Hons) from the University of Canterbury, Christchurch, New Zealand and her PhD in synthetic organic chemistry from the Research School of Chemistry, Australian National University, Canberra under the mentorship of the late Professor Athel Beckwith, FRS. Following her PhD, she was awarded a Samuel and Violette Glasstone Research fellowship at the University of Oxford, UK where she studied bioorganic reaction mechanisms.  This was followed by a Faculty position in the Department of Chemistry, Victoria University of Wellington, NZ (1991-1993) and the Department and Research School of Chemistry, Australian National University (1994-2004) where she was Associate Professor.

 

She joined the Institute of Chemical and Engineering Sciences as a Principal Scientist and Programme Manager of the New Synthesis Techniques and Applications (NSTA) Programme from 2004 till 2011. From 2008-2011, she also held a co-appointment as Director of Graduate Affairs, Science and Engineering Research Council, A*STAR. From August 2011-Dec 2015, Prof Chai held a joint appointment as Associate Professor in the Department of Pharmacy, National University of Singapore and the Institute of Chemical and Engineering Sciences, A*STAR. She was Deputy Head of Department from Jan 2013-April 2014 and Assistant Dean in the Faculty of Science, NUS, from June 2013 till Dec 2015. Prof Chai is currently Head of Department since Jan 2016.

Synthesis of natural products

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Natural products or natural product derived drugs comprised 32% of small molecule approved drugs between 1981 and 2010. In the same period of time, 16% of small molecule approved drugs were synthetic or natural mimics based on the study of pharmacophores related to natural products. Indisputably, natural products provide diverse structural diversity and intricate carboskeletal frameworks. As it is believed that nature has evolved optimized biologically active compounds – the secondary metabolites – to ensure survival of the species that produce them, natural products are perceived as more ‘drug-like’ than totally synthetic compounds. As such, natural products may provide us with the ‘best’ lead compounds yet for drug discovery, giving rise to natural product inspired drug design. Our efforts are directed towards the development of selected natural products in lead identification. Examples of these natural products are calothrixins, cordypyridones, hybocarpone, scabrosin esters.
Representative publications:

  • P.H. Bernardo and C.L.L. Chai, ‘Friedel-Crafts Acylation and Metalation Strategies in the Synthesis of Calothrixins A and B’, J. Org. Chem., 2003, 68, 8906-8909.
  • C.L.L. Chai, J.A. Elix and F.K. Moore, ‘Concise Formal Total Synthesis of Hybocarpone and Related Naturally Occurring Naphthazarins’, J. Org. Chem., 2006, 71, 992-1001.
  • N.Q. Vu, C.L.L. Chai, K.P. Lim, S.C. Chia and A. Chen, ‘Highly convergent and practical total synthesis of Aigialomycin D’, Tetrahedron, 2007, 63, 7053-7058.

 

New cancer chemotherapeutics

Cancer is a complex disease to cure and there are many facets to the disease that make the development of cancer chemotherapeutics a challenge. Our approaches are mainly target based approaches as briefly outlined below:

(i) Small molecule inhibitors of the Bcl-2 family

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In recent years, the Bcl-2 family of pro-survival proteins has gained considerable interest as viable drug targets for cancer chemotherapy. It is thus not surprising that intense efforts have focused on the development of Bcl-2 inhibitors for cancer chemotherapy. One of the most promising inhibitors to date is ABT-737 and its orally active congener, ABT-263. These compounds were developed by Abbott Laboratories and ABT-263 is currently in Phase I clinical trials. Interestingly, ABT 737 and ABT-263 are potent inhibitors of multiple members of the pro-survival proteins of the Bcl-2, but they do not inhibit Mcl-1. It has also been observed that cancer cells that are resistant to the cytotoxic activity of ABT-737 become remarkably sensitive towards ABT-737 when the level of Mcl-1 protein in cancer cells is neutralized. This suggests that a selective inhibitor of Mcl-1, in conjunction with ABT-737, could constitute a powerful anti-cancer therapy against a large spectrum of cancers. To date, no selective small molecule inhibitor of Mcl-1 has been reported. This is in part because little is known on the structural determinants that govern the selectivity of the different members of the Bcl-2 proteins. The proposed research will build on our previous discoveries in this area. We will utilize a combination of rational drug design, molecular modeling to identify and synthesise highly potent and highly selective Mcl-1 inhibitors.
Representative publication:

  • P.H. Bernardo, T. Sivaram, K.-F. Wan, J. Xu, J. Krishnamoorthy, C.M. Song, L. Tian, J.S.F. Chin, D.S.W. Lim, H.Y.K. Mok, V.C. Yu, J.C. Tong, C.L.L. Chai, ‘Structural insights into the design of small molecule inhibitors that selectively antagonize Mcl-1’, J. Med. Chem, 2010, 53, 2314-2318.

 

(ii) Small molecules for epigenetic therapy

Epigenetics are heritable changes in gene expression that do not result from alteration in the DNA sequence. These alterations play important roles in cancer development as many tumor suppressors have been found to be inactivated by epigenetic silencing and hence this provides cancer cells with selective advantages for survival, growth and colonization. Unlike cancer-causing genetic mutation, epigenetically silenced tumor suppressor genes can be reactivated. This has opened up new possibilities for the development of epigenetic drugs in which undesired epigenetic modifications are targeted for therapeutic intervention.
Representative publication:

  • E.K.W. Tam, Z. Liu, Y.L. Goh, X. Cheng, S.Y. Wong, S. Santhakrishnan, C.L.L. Chai, S.Q. Yao, ‘Cell-Based Proteome Profiling Using an Affinity-Based Probe (AfBP) Derived from 3-Deazaneplanocin A (DzNep)’, Chemistry –An Asian Journal , 2013, 8, 1818-1828.

 

(iii) Development of kinase inhibitors

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Recent biological and computational advances in drug design have revitalized targeted covalent inhibition as very efficient and practical approaches for the development of kinase inhibitors as new drugs. Consequently, covalent inhibitor drugs are more widely accepted now than a decade ago, as is evidenced by the approval of two targeted covalent kinase inhibitors Afatinib and Ibrutinib as anticancer drugs in 2013 alone. Our group is interested in a class of 14-membered macrocyclic natural products called resorcylic acid lactones (RALs) which has attracted the attention of both academia and pharmaceutical companies due to their intriguing biological attributes.

Representative publications:

  • J. Xu, A. Chen, M.L. Go, K. Nacro, B. Liu, C.L.L. Chai, ‘Exploring Aigialomycin D and Its Analogues as Protein Kinase Inhibitors for Cancer Targets’, ACS Medicinal Chemistry Letters, 2011, 2, 662-666.
  • J. Xu, A. Chen, J. Joy, V.J. Xavier, E.H.Q. Ong, J. Hill, C.L.L. Chai, ‘Rational Design of resorcylic acid lactone analogues as covalent MNK1/2 inhibitors by tuning the reactivity of an enamide Michael acceptor’, ChemMedChem, 2013, 8, 1483-1494.

 

Anti-infectives

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Infectious diseases continue to plague mankind despite the availability of previous groundbreaking treatments for some of these diseases. Bacterial infections and malaria were major diseases which were largely under control in the past. However due to the emergence of drug resistant organisms, these diseases are now a threat to mankind. Thus there is an urgent need to develop new drugs for the treatment of bacterial infection (including tuberculosis), malaria, viral diseases (such as AIDS, Chikungunya, Dengue). In our laboratories, we are interested in the discovery of new scaffolds for use in drug development for treatment of some of these infectious diseases. In addition, we are also examining strategies for the prevention of bacterial infection through specially modified surfaces for applications in medical devices and equipment.
Representative publication:

  • B.S.W Tan, C.L.L. Chai, M.G Moloney, ‘Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity’, Org. Biomol. Chem., 2014, 12, 1711-1716.

 

Stem cell differentiation

The aim of this project is to design and synthesise small molecules for stem cell studies and applications. Stem cell therapy for potential regenerative medicine applications has been hailed as having enormous promise in the future treatment of numerous diseases from cardiovascular to neurodegenerative diseases. However for progress to be made, a greater understanding of stem cell chemistry and biology is needed. Specifically, some of the challenges that are faced include limited cell availability and the ability to control the fate of stem cells. Small molecules have been shown to be effective in the selective control of stem cell proliferation and differentiation. Some compounds such as reversine are capable of de-differentiating lineage committed cells to multi potent progenitor cells. This discovery suggests the possibility for potentially limitless supply of any cells that are desired and thus can circumvent the issue of supply as well as ethical considerations with the use of hESCs.
Representative publication:

  • J.L. Low, G. Jurjens, J. Seayad, J. Seow, S. Ting, F. Laco, S. Reuveny, S. Oh, C.L.L. Chai, ‘Tri-substituted imidazole analogues of SB203580 as inducers for cardiomyogenesis of human embryonic stem cells’, Bioorg. Med. Chem. Lett., 2013, 23, 3300-3303.

 

Neurodegenerative diseases

There is an increasing realization that effective treatment of complex diseases requires multi-targeted approaches. This is because in a complex disease network, targeting the inhibition of a particular protein may not be sufficient to restore the system to normality. Thus for optimal therapeutic benefits, approaches based on polypharmacology are likely to be more effective. Although combination treatments have long been used to achieve this purpose, the design of a single chemical entity that can act simultaneously at multiple molecular targets are less common due to the complexities in design. These compounds termed as ‘multi-targeted’ drugs, are less prone to drug resistance and should be more efficacious due to synergistic effects. Neurodegenerative diseases such as Parkinson disease, Alzheimer’s disease are examples of complex diseases that may require multi-targeted approach to be effective. These diseases are characterized by the progressive loss of neurons and typically occur in the elderly population, therefore, their incidence is continuously rising in industrialized countries. In collaboration with scientists in Hungary, we are interested in the development of multi-targeted ligands for the treatment of Parkinson’s disease.

Representative publication:

  • P. Dunkel, C.L.L. Chai, B. Sperlagh, P.B. Huleatt, P. Matyus, ‘Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis’, Expert Opinion on Investigational Drugs, 2012, 21, 1267-1308.

Research Staff

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HO Thanh Tu (Research Assistant)
Email: phahott@nus.edu.sg

 

Postgraduate Students

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Ching Kuan Chieh (PhD student)
Email: a0046534@nus.edu.sg

 

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Lyu Qinghua (PhD student)
Email: a0129473@u.nus.edu

 

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Zhong Qixing (PhD student)
Email: zhong_qixing95@nus.edu.sg