Fact and Figures
Malaysia is one of the 12 mega-diversity centres and is home to 10% of living organisms in the world. With an estimated 15,500 species of higher plants, 300 species of mammals and 189 species of amphibians. Embedded within the variety of flora and fauna are diverse chemicals that may be developed into clinically useful drugs. Significantly, 74% of all anticancer compounds in use are derived in some ways from natural sources.
- Newman, D. J. and Cragg, G. M., Journal of Natural Products, 75, 311, 2012
Significantly, 74% of all anticancer compounds in use are derived in some ways from natural sources. Notable examples include camptothecin, etoposide, vinblastine and paclitaxel. Realising this, the Drug Discovery Team in Cancer Research Malaysia started a program in year 2004, to tap into Malaysia’s biodiversity for potential anti-cancer drugs. The current efforts are focused on a work flow that can be effectively used to screen large libraries of screen natural products that can potentially offer targeted anticancer therapies.
The approaches used include a zebrafish phenotypic assay, used essentially as a multi-pathway screening model, while another approach utilizes a cell-based synthetic lethality assay to search for new and novel inhibitors that are specific for cancers with defective DNA repair. A novel approach currently being implemented is seeking inhibitors of the enzyme APOBEC3B that is now recognized as a causal molecule in several cancers. Find out more below:
Reversing non effective anticancer therapies, reversing the time taken to develop effective anticancer therapies, reversing the serious side effects of current anticancer therapies
Both preclinical and clinical data have shown a preferential anti-tumor effect on BRCA1 and BRCA2 deficient tumors, by a PARP1 inhibitor, which is a small molecule that inhibits the function of PARP enzyme. This is currently one of the best examples of a synthetic lethal approach of cancer therapeutics and it has already entered into Phase II clinical studies.
Synthetic lethality, defined as the lethal effect of inactivating two enzymes or pathways when inactivation of either one alone is tolerated, has major potential for cancer therapy. Broadly, mutant cancer-related genes can sensitise tumour cells to a class of drugs that can specifically inhibit the synthetic lethal partner without affecting normal cells, thus allowing higher therapeutic selectivity.
- The goal of this project is to identify small molecules from natural products that can target genomic aberrations of cancers through a synthetic lethality approach. Furthermore, we aim to unravel the underlying mechanism of action for the most bioactive constituents using genetic and biochemical methods.
For this strategy, the Drug Discovery team aims screen extracts and structurally diversified compounds from our current library to identify any potent synthetic lethality candidates using relevant isogenic human cell lines harboring genetic defects that includes genetic instability as well as cell cycle and cell signalling defects.
- Currently, we are using engineered isogenic cell-lines in our screening program for discovery and development of natural products that can behave as synthetic lethal partners to BRCA2, thereby allowing selective targeting of cancer cells with defective BRCA2 while sparing the normal cells.
- CURRENT PROJECTS
- 1. To screen, identify, isolate and characterize putative synthetic lethality molecules from natural products.
- 2. To unravel the underlying mechanism of action of the bioactive constituents.
- 3. To evaluate the synthetic lethal effect of the bioactive constituents in suitable mouse models of human cancers.
Zebrafish phenotypic assay is one way to discover new target specific anti-cancer compounds from natural products.
Since embryogenesis and carcinogenesis have common critical pathways, a chemical that interferes with embryogenesis could also affect the development of cancer in a pathway-specific manner. The zebrafish embryo is ideal for such phenotypic assays because the embryos are transparent thereby allowing easy observation of their development and any defects arising from exposure to natural products.
- The main goal of project is to identify potential drug candidates that specifically target the conserved signalling pathways involved in human carcinogenesis and zebrafish embryogenesis as well as inhibitors of tumor angiogenesis and lymph angiogenesis
The work focuses on using zebrafish developmental phenotypic and angiogenic assays for the identification of potential bioactive natural product samples. After, using secondary biochemical assays using suitable human cancer cell lines for validating hits from the phenotypic assay.
- This is possible by screening natural products for the appearance of abnormal phenotypes in developing zebrafish embryo which if observed that this is an indication of chemical disruption on specific embryo developmental genes in zebrafish.
- CURRENT PROJECTS
- 1. Zebrafish developmental phenotypic and angiogenic assays for the identification of potential bioactive natural product samples.
- 2. Zebrafish phenotypic and angiogenesis assay optimization using known chemical pathway inhibitors.
- 3. Secondary assays for validating hits identified from zebrafish phenotypic assay and literature aided target pathway identification.
The cytosine deaminase APOBEC3B (A3B) enzyme, has been reported to be overexpressed in several cancers including breast cancer and all featuring the mutational signature associated with A3B activity. Hence, one hitherto unexplored area is that inhibitors for A3B may prevent mutations that lead to specific cancer evolution and that these inhibitors may be clinically useful in the prevention and progression of certain solid cancers.
The overall goal in this project is setup and optimize a quantitative assay based on Forster Resonance Energy Transfer (FRET) for monitoring deaminase activity of A3B.
Using FRET to search for active molecules in our in-house library of natural product extracts and compounds that are capable of inhibiting A3B activity. Promising candidates will be further subjected to very stringent evaluation of potency of inhibition in in vitro and in vivo assays. The overarching goal of this proposed study is to identify and vlaidate molecules that are able to inhibit the enzymatic activity of APOBEC3B.
- 1. “Prioritization of Natural Extracts by LC/ MS-PCA for the Identification of New Photosensitizers for Photodynamic Therapy” Norazwana Samat, Pei Jean Tan, Khozirah Shaari, Faridah Abas, Hong Boon Lee, Analytical Chemistry 2014, 86(3), 1324-1331 (doi: 10.1021/ac403709a) [Editor’s Highlight].
- 2. “Rosamines Targeting the Cancer Oxidative Phosphorylation Pathway” SH Lim, LX Wu, LV Kiew, LY Chung, K Burgess, HB Lee, PLoS One 2013, accepted.
- 3. “Ternary copper(II)-polypyridyl enantiomers: Aldol condensation, characterization, DNA-binding recognition, BSA-binding and anticancer property” Ng CH, Wang WS, Chong KV, Win YF, Neo KE, Lee HB, San SL, Raja Abd Rahman RN, Leong WK, Dalton Transaction June 2013,accepted
- 4. “Photodynamic Activity of Plant Extracts from Sarawak Borneo” Wan Wui Jong, Pei Jean Tan, Fadzly Adzhar Kamarulzaman, Michele Mejin, Diana Lim, Ida Ang, Margarita Naming, Tiong Chia Yeo, Anthony Ho Siong Hock, Soo Hwang Teo and Hong Boon Lee Chemistry & Biodiversity 2013, accepted.
- 5. “Phylogeny of Asian Homalomena (Araceae) based on ITS region combined with morphological and chemical data” Wong Sin Yeng, Tan Pei Jean, Ng Kiaw Kiaw, Ahmad Sofiman Othman, Lee Hong Boon, Fasihuddin Badruddin bin Ahmad & Peter Charles Boyce Systematic Botany 2013, accepted.
- 6. “Chemical Constituents from the bark of Aglaia lanuginose” Fadzly Adzhar Kamarulzaman, Khalit Mohamad,Khalijah Awang, Hong Boon Lee Journal of Science & Technology 2013, accepted.
- 7. “Synthesis and in vitro anticancer studies of novel C-2 arylidene congeners of lantadenes” Navin K. Tailor, Hong L. Boon, Manu Sharma, European Journal of Medicinal Chemistry 2013, 64, 285–91.
- 8. “Effective melanoma inhibition by synthetic pentacyclic triterpenoid 2-(3-phenylprop-2-en-1-ylidene)-22β-hydroxy-3-oxoolean-12-en-28-oic acid: An in vitro and in vivo study ” Tailor NK, Lee HB, Sharma M, J Environ Pathol Toxicol Oncol 2013, 32(1):59-72.
- 9. “Synthesis, selective cancer cytotoxicity and mechanistic studies of novel analogs of lantadenes” Navin Kumar Tailor, Varun Jaiswal, San Swee Lan,Hong Boon Lee, Manu Sharma, Anticancer Agents Med Chem. 2013, 13(6):957-66.
- 10. “BODIPY Dyes in Photodynamic Therapy” Anyanee Kamkaew, Siang Hui Lim, Hong Boon Lee, Lik Voon Kiew, Lip Yong Chung, Kevin BurgessChem. Soc. Rev. (2012), DOI:10.1039/C2CS35216H.
- 11. “[Zn(phen)(O,N,O)(H2O)] and [Zn(phen)(O,N)(H2O)] with O,N,O = 2,6-dipicolinate and N,O = L-threoninate: synthesis, characterization, biomedical properties” Lee-Fang Chin, Siew-Ming Kong, Hoi-Ling Seng, Yee-Lian Tiong, Kian-Eang Neo, Mohd Jamil Maah, Alan Soo-Beng Khoo, Munirah Ahmad, Tzi-Sum Andy Hor, Hong-Boon Lee, Swee-Lan San, Soi-Moi Chye and Chew-Hee Ng J Biol Inorg Chem (2012), DOI 10.1007/s00775-012-0923-y.
- 12. “Two New Phloroglucinol Derivatives and Five Photosensitizing Pheophorbides from Syzygium polyanthum Leaves (Salam)” Lee Wei Har, Intan S. Ismail and Lee Hong Boon Natural Product Communications (2012), MS#P083412 accepted.
- 13. “DNA molecular recognition and cellular selectivity of anticancer metal(II) complexes of EDDA and phenanthroline: multiple targets” Sze-Tin Von, Hoi-Ling Seng, Hong-Boon Lee, Seik-Weng Ng, Yusuke Kitamura, Makoto Chikira, Chew-Hee Ng J Biol Inorg Chem (2012), 17(1):57-69.
- 14. “Cyclic Tetrapyrrolic Photosensitisers from Cladophora patentiramea (Cladophoraceae, Chlorophyta) and Turbinaria conoides (Sargassaceae, Phaeophyta) for Photodynamic Therapy” Y.V.Tang, S.M.Phang, W.L.Chu, A.S.H.Ho, S.H.Teo, H.B.Lee. Journal of Applied Phycology (2012), 24(4):783-90.
- 15. “Rapid Identification of Photosensitisers for Photodynamic Therapy using On-Line Hyphenated LC-PDA-MS coupled with photo-cytotoxicity assay” P. J. Tan, D. R. Appleton, M. R. Mustafa, H. B. Lee. Phytochemical Analysis (2012), 23(1):52-9.
- 16. “Validation of Quantitative Structure-Activity Relationship (QSAR) Model for Photosensitizer Activity Prediction” Neni Frimayanti, Mun Li Yam, Hong Boon Lee, Sharifuddin M. Zain and Noorsaadah Abdul Rahman Int. J. Mol. Sci. (2011), 12, 8626-8644.
- 17. “Cyclic Tetrapyrrolic Photosensitisers from the leaves of Phaeanthus ophthalmicus” Pei Jean Tan, Cheng Yi Ong, Asma Danial, Hirzun Mohd Yusof, Bee Keat Neoh, Hong Boon Lee. Chemistry Central Journal (2011), 5(1):32.
- 18. “A New Naturally-derived Photosensitiser and Its Phototoxicity on Head and Neck Cancer Cells” Siang Hui Lim, Hong Boon Lee, Anthony Siong Hock Ho. Photochemistry and Photobiology (2011), 87(5):1152-8.
- 19. “Derivatives of Pheophorbide-a and Pheophorbide-b from Photocytotoxic Piper penangense Extract.” Adzhar Kamarulzaman F, Shaari K, Siong Hock Ho A, Haji Lajis N, Hwang Teo S, Boon Lee H. Chem Biodivers. (2011) Mar;8(3):494-502.
20. “In vitro and in vivo photocytotoxicity of boron dipryromethene derivatives for photodynamic therapy.” Lim SH, Thivierge C, Nowak-Sliwinska P, Han J, van den Bergh H, Wagnières G, Burgess K, Lee HB. J Med Chem. (2010) Apr 8;53(7):2865-74.
- 21. “The neovessel occlusion efficacy of 15-hydroxypurpurin-7-lactone dimethyl ester induced with photodynamic therapy” Lim SH, Nowak-Sliwinska P, Kamarulzaman FA, van den Bergh H, Wagnières G, Lee HB. Photochem Photobiol. (2010) Mar-Apr;86(2):397-402. Epub 2010 Jan 13.
- 22. “The Search for Novel Photosensitisers from Malaysian Plants and Microorganisms” Hong Boon Lee, Nurkhalida Kamal, Cheng Yi Ong, Vikineswary Sabaratnam, Noorlidah Abdullah, Sui Kiong Ling, Rasadah Mat Ali, Anthony S. H. Ho, Soo Hwang TeoMalaysian Journal of Science 2009, 28:129-45.
- 23. “New Cytotoxic Rosamine Derivatives Selectively Accumulate in Mitochondria of Cancer Cells” SH Lim, L Wu, K Burgess, HB Lee. Anticancer Drugs(2009) 20(6): 461 – 8
- 24. “Systematic analysis of in vitro photo-cytotoxic activity in extracts from terrestrial plants in Peninsula Malaysia for photodynamic therapy” CY Ong, SK Ling, R Mat Ali, CF Chee, Z Abu Samah, ASH Ho, SH Teo, HB Lee J. Photochem. Photobiol. B (2009) 96(3):216-22.
- 25. “Light-activated Cytotoxic Compounds from Malaysian Microorganisms for Photodynamic Therapy (PDT) of Cancer” N Kamal, V Sabaratnam, N Abdullah, ASH Ho, SH Teo and HB Lee. Antonie van Leeuwenhoek (2009) 95(2):179-88.
- 26. “Screening of Red Extracts from Actinomycetes and Fungi for Photodynamic Therapy” CY Ong, SE How, SH Puah, SH Mahassan, K Suppayah, HH Teoh, NK Wong, SH Teo, ASH Ho, HB Lee and CC Ho Beyond Medicinal Plants University Publication Centre (UPENA) UiTM (2008) 27-34
- 27. “Screening of Selected Species of Malaysian Medicinal Plants for Photodynamic Properties” SK Ling, CF Chee, HB Lee, ASH Ho, MA Rasadah, AS Zainon, MGH Khoo and A Norhayati Highlights of FRIM’s Non-IRPA Projects (2006) 53-7
- 28. “p53 status does not affect photodynamic cell killing induced by Hypericin” HB Lee, ASH Ho, SH Teo. Cancer Chemother Pharmacol. (2006) 58, 91-8
- 29. “Photo-cytotoxic pheophorbide-related compounds from Aglaonema simplex” CF Chee, HB Lee, HC Ong, ASH Ho. Chemistry & Biodiversity (2005) 2, 1648-55.