Drug Discovery and Development
Cervical-Cancer-cells

Drug Discovery and Development

Our research programs are directed towards the discovery and development of new drugs for a range of therapeutic applications, particularly cancer. This involves multidisciplinary approaches using structure-guided medicinal chemistry, target-driven cellular and animal pharmacological evaluations. The combination of capabilities in computational drug design, medicinal chemistry, cellular and animal pharmacology and toxicology in the single cohesive research laboratory holds the promise for rapid advancement of drug discovery and development in an effort to identify drug candidates and novel therapeutic targets.

Current research projects

  • Pharmacological inhibitors of Mnk for treatment of cancer. (MAPK)-interacting kinase (Mnk) is responsible for many types of human cancers.  Inhibition of Mnk activity provides effective anti-cancer strategy. We have recently identified a class of heterocyclic compounds that potently and selectively inhibit Mnk activity. We aim to optimise the current chemical series for specificity and drug-like properties and to provide pre-clinical lead compounds for treatment of haematological cancer and solid tumour. 
  • Development of cell-cycle CDK inhibitors as anti-cancer agents.  Discovery of cyclin-dependent kinases (CDKs) as key regulators of the cell cycle was made by Hartwell, Nurse and Hunt, which earned them a Nobel Prize in Physiology & Medicine in 2001. Tumour-associated cell-cycle defects are mediated by alterations in CDK activity. Although many CDK inhibitors have been identified, little progress has been made in the discovery mono-specific inhibitors. The aim of this project is to design and synthesise the novel classes of drug candidates that target individual cell-cycle CDKs specifically and can be developed as targeted cancer therapeutics. 
  • Targeting transcriptional CDK9 for cancer treatment. Apoptosis is a cell suicide program essential for the regulation of development and the prevention of tumorigenesis. Evading the apoptotic program is a hallmark of cancer and is often mediated by up-regulation of anti-apoptotic proteins. Metastatic castration-resistant prostate cancer (CRPC) is an incurable condition characterized by impaired apoptosis and increased expression of anti-apoptotic proteins. We have shown that inhibition of CDK9, a key regulator of RNA polymerase II (RNAPII) transcription, can induce CRPC cell apoptosis. This project aims to identify mono-specific CDK9 inhibitors for treatment of metastatic castration-resistant prostate cancer.
  • Development of mitotic inhibitors as anti-cancer agents. The targeted cancer therapeutical agents have the advantage of reduced side effects; however, the genetic instability of cancer allows mutation to occur which develop resistance to the therapies. Targeting the key components of signalling pathways that are critical for cancer cell survival has been proposed as an effective anti-cancer strategy, particularly for treatment of the advanced diseases. We have developed a novel class of small molecules that showed high potencies against a panel of human cancer cells lines. The lead compounds target cellular key regulators of cell-cycle mitotic pathways and effectively induce cancer cell apoptosis. Importantly, the lead compounds demonstrated the favourable drug-like properties with high oral bioavailability. This project aims to evaluate pre-clinical anti-tumour efficacy and toxicity for potential clinical studies.

 

Recent publications

F. Lam, A.Y. Abbas, H. Shao, T. Teo, J. Adams, P. Li, T.D. Bradshaw, P.M. Fischer, E. Walsby, C.Pepper, Y. Chen, J. Ding and S. Wang. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget, Vol. 5, No. 17, 2014.

S. Diab, M. Kumarasiri, M. Yu, T. Teo, C. Proud, R. Milne, and S. Wang. MAP Kinase-interacting kinases: emerging targets against cancer. Chemistry & Biology, 21, 441-452, DOI:10.1016/j.chembiol.2014.01.011, 2014.

T. Lu, A. Goh, M. Yu, J. Adams, F. Lam, T. Teo, P. Li, B. Noll, L. Zhong, S. Diab, O. Chahrour, A. Hu, A. Y. Abbas, X. Liu, S. Huang, C. J. Sumby, R. Milne, C. Midgley, and S. Wang. (2014) Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anti-cancer agents: synthesis, structure-activity relationships, and biological activities. Journal of Medicinal Chemistry,57, 2275-2291, dx.doi.org/10.1021/jm4019614, 2014.

S. Diab, T. Teo, M. Kumarasiri, P. Li, M.Yu, F. Lam, S. Basnet, M. J. Sykes, H. Albrecht, R. Milne, and S. Wang. Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk inhibitors: synthesis, SAR analysis and biological evaluation. ChemMedChem, DOI:10.1002/cmdc.201300552, 2014

Lu, T., Laughton, C.A., Wang, S., Bradshaw, T.D. In vitro Anti-tumour Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide. Mol Pharmacol, pii: mol.114.093245, 2014.

E. Walsby, G. Pratt, H. Shao, A. Y. Abbas, P. M. Fischer, T. D. Bradshaw, P. Brennan, C. Fegan, S. Wang, and C. Pepper. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget, DOI:1568 [pii], 2013.

H. Shao, S. Shi, D. W. Foley, F. Lam, A. Y. Abbas, X. Liu, S. Huang, X. Jiang, N. Baharin, P. M. Fischer, and S. Wang. Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents. European Journal of Medicinal Chemistry, 10.1016/j.ejmech.2013.08.052, 2013.

J. Hou, T. Teo, M. J. Sykes, and S. Wang. Insights into the Importance of DFD-Motif and Insertion I1 in Stabilizing the DFD-Out Conformation of Mnk2 Kinase. ACS Medicinal Chemistry Letters, dx.doi.org/10.1021/ml400145x, 2013.

Shao, H., Shi, S., Huang, S., Hole, A., Abbas, A. Y., Baumli, S., Liu, X., Lam, F., Foley, D. W., Fischer, P. M., Noble, M., Endicott, J. A., Pepper, C., Wang, S., Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, x-ray crystal structures, SAR and anti-cancer activities. Journal of Medicinal Chemistry. DIO:10.1021/jm301475f, 2013.

Wang S., and Shao, H. Therapeutic compounds, WO2013156708A1, 2013.

Hole, A., Baumli, S., Shao, H., Shi, S., Pepper, C., Fischer, P. M., Wang, S., Endicott, J. A., Noble, M., Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotope selectivity. Journal of Medicinal Chemistry. DOI:10.1021/jm301495v, 2013.