Drug Development Unit

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	Haishan WANG
	Lab Location: #8-07 email: hswang@imcb.a-star.edu.sg tel: 65869718
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	Key Publications
	Wang, H.; Yu, N.; Chen, D.; Lee, K. C. L.; Lye, P. L.; Chang, J. W. W.; Deng, W.; Ng, M. C. Y.; Lu, T.; Khoo, M. L.; Poulsen, A.; Sangthongpitag, K.; Wu, X.; Hu, C.; Goh, K. C.; Wang, X.; Fang, L.; Goh, K. L.; Khng, H. H.; Goh, S. K.; Yeo, P.; Liu, X.; Bonday, Z.; Wood, J. M.; Dymock, B. W.; Ethirajulu, K.; Sun, E. T. Discovery of (2E)-3-{2-Butyl-1[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxy acrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile. J. Med. Chem. 2011, 54, 4694-4720. Jayaraman, R.; Reddy, V. P.; Pasha, M. K.; Wang, H.; Sangthongpitag, K.; Yeo, P.; Hu, C. Y.; Wu, X.; Xin, L.; Goh, E.; New, L. S.; Ethirajulu, K. Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics. Drug Metab. Dispos 2011, 39, 2219–2232. Wang, H.; Lim, Z.-Y.; Zhou, Y.; Ng, M.; Lu, T.; Lee, K.; Sangthongpitag, K.; Goh, K. C.; Wang, X.; Wu, X.; Khng, H. H.; Goh, S. K.; Ong, W. C.; Bonday, Z.; Sun, E. T. Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity. Bioorg. Med. Chem. Lett. 2010, 20, 3314-3321. Wang, H.; Dymock, B. W. New patented histone deacetylase inhibitors. Expert Opin.Ther. Pat. 2009, 19, 1727-1757. Novotny-Diermayr, V.; Sangthongpitag, K.; Hu, C. Y.; Wu, X.; Sausgruber, N.; Yeo, P.; Greicius, G.; Pettersson, S.; Liang, A. L.; Loh, Y. K.; Bonday, Z.; Goh, K. C.; Hentze, H.; Hart, S.; Wang, H.; Ethirajulu, K.; Wood, J. M. SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer. Mol. Cancer Ther. 2009, 9, 642-652. Wang, H.; Usui, T.; Osada, H.; Ganesan, A. Synthesis and evaluation of tryprostatin B and demethoxyfumitremorgin C analogues. J. Med. Chem. 2000, 43, 1577-1585. Wang, H.; Lim, K. L.; Yeo, S. L.; Xu, X.; Sim, M. M.; Ting, A. E.; Wang, Y.; Yee, S.; Tan, Y. H.; Pallen, C. J. Isolation of a novel protein tyrosine phosphatase inhibitor, 2-methyl-fervenulone, and its precursors from Streptomyces. J. Nat. Prod. 2000, 63, 1641-1646. Wang, H.; Ganesan, A. A biomimetic total synthesis of (-)-spirotryprostatin B and related studies. J. Org. Chem. 2000, 65, 4685-4693. Wang, H.; Ganesan, A. The N-acyliminium Pictet-Spengler condensation as a multicomponent combinatorial reaction on solid phase and its application to the synthesis of demethoxyfumitremorgin C analogues. Org. Lett. 1999, 1, 1647-1649. Wang, H.; Ganesan, A. Total synthesis of the quinazoline alkaloids (-)-fumiquinazoline G and (-)-fiscalin B. J. Org. Chem. 1998, 63, 2432-2433.
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			Haishan WANG
			Haishan Wang received his B.Sc. from Beijing Medical University in 1986, and Ph.D. from Peking Union Medicinal College and Chinese Academy of Medical Sciences in 1991. He worked on design, synthesis, and development of novel quinolone and beta-lactam antibiotics at the Institute of Medicinal Biotechnology, Beijing, as a Research Assistant (1991), as a Research Associate (1992-1994), and as an Associate Investigator (1994-1995). He spent one year working on asymmetric synthesis at Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-Yvette, France. He then moved to Singapore and worked on medicinal, combinatorial, and natural product chemistry projects at IMCB, as a Research Fellow (1996-2000) and as a Research Associate (2000-2001). In October 2001, he joined S*BIO Pte Ltd as a Group Leader in medicinal chemistry. As a Project Leader, he together with the histone deacetylase (HDAC) project team delivered the development candidate SB939 (pracinostat) and two other preclinical development candidates (PDCs). Pracinostat has an excellent preclinical profile and is now in phase II clinical trials. Besides HDAC inhibitors, he also worked on inhibitors of kinases (e.g., CDK2, PLK, Aurora, PDK, JAK2, and PI3K/mTOR) and other cancer relevant targets. In December 2011, he joined IMCB to set up and head the Drug Development Unit (DDU).

			Drug Research and Development
			The DDU lab operates like a mini biotech company for its drug R&D projects, but enjoys the freedom of an academic research environment and abundant biological resources available for collaborative projects. *Anticancer and anti-infective agents* We are interested in the design, synthesis, and development of a type of molecule that we call “probability” drug which can improve the efficacy of a given treatment or lower the probability of drug resistance by acting on two and more pathways or targets, at least one of which is a proven pathway or validated target. These targets include those we have previously worked on such as epigenetic targets (e.g., HDAC) and kinases as well as others that are available and doable at IMCB. These projects are initially chemistry-driven and the ultimate goal is to deliver novel (i.e., patentable) drug candidate up to PDC stage for further development, collaboration, and partnership. *Early stage drug discovery and development* We work closely with interested labs to advance their translational research on new biological functional targets and hits identified at IMCB. We offer a broad range of expertise in drug R&D (see details in our Capabilities). We can help with target validation/identification by chemical approaches. We also understand there is an urgent need of quality compounds for hits generation. For the initial screening and target validation/identification, we are selecting compounds we have made in-house as well as commercially available compounds to generate a modest collection of small molecules for major or popular drug targets or biological pathways. Tool compounds and (labelled) substrates may be made or modified to support the target validation/identification (e.g., finding targets for known drugs) and assay development; these are also near term deliverables. *Drug screening platform and technology* The DDU lab is currently collaborating with other leading labs and working on drug absorption and metabolism in order to establish an alternative toxicity evaluation model. Besides above-mentioned tool compounds or probes, we are also interested in synthesis of antigens for small molecule antibodies, developing or improving chemistries for new or existing assays and diagnostic tools for future collaborative projects at IMCB.


	(Click to view larger images)
	Example of lead optimization: discovery of pracinostat (SB939), an HDAC inhibitor. Fig. (a) Level of acetylated histone 3 (AcH3) in COLO205 cells correlates with inhibitory potency against HDAC1, p = 0.0058 (b) Anti-proliferative cellular potency correlates with enzyme inhibitory potency, p <0.0001 (c) Human liver microsomal stability (t1/2) correlates with compound’s lipophilicity (clogP), p = 0.0152. (d) Pracinostat docked into an HDAC1 homology model and two key interactions between two basic centres are shown.