Research Projects
Development of Dual Acting Single Molecule Drugs
Title: Proof of concept of the transient drug applied to oncology
Funding: NMRC CBRG Grant (Co-PI: Prof Sten Ohlson, School of Biological Sciences, NTU)
Lianbin Yao and Kalaipriya: The use of weak affinity chromatography tandem mass spectrometry (WAC-MS) to discover and characterize weak binders to established oncology targets from different signaling pathways JAK2, HDAC and HSP90. Synthesis and study of different combinations of single molecules each with a ‘dual action’ will be undertaken to explore the concept of weaker inhibition of individual biological targets but overall a potent effect on the cell phenotype with lower toxicity.
Title: Design and Synthesis of dual acting drugs
Funding: Start-Up grant
Eugene Yang and Joy Chu: Specific molecules will be designed from known potent drugs and fragments of those drugs. Objective is to obtain novel compounds that have high-high, high-low, low-high and low-low activities for both targets such as JAK2/HDAC. In total there are 6 different combinations of dual acting inhibitors planned. So far we have learned that it is possible to obtain novel and surprising isoform selectivity combinations depending on the molecular design strategies (unpublished work).
Development of G9a Methyltransferase Inhibitors for the treatment of Muscular Dystrophy and Cancer
Uttara: Histone methyltransferases (HMT) like G9a catalyze the methylation of histone amino acid residues, one of the important post translational modifications in epigenetic signalling. G9a levels are found to be elevated in pathological conditions like cancer and muscular dystrophy. Furthermore, the malaria parasite is also susceptible to HMT inhibition. Nanomolar potent quinazolines (Univ of North Carolina, Figure below) have been reported acting via binding to the peptide (substrate) binding site (BIX, UNC series (Vedadi et al., Nature Chem. Bio., 2011, 7, 566-575)). Amino-indole inhibitors of G9a (Abbvie) are also very potent and especially compact molecule Give ref for amino-indoles (Sweis et al., ACS Med Chem Letters, 2014). We have initially employed a scaffold hopping strategy to discover novel G9a inhibitor templates by taking into account the various interactions with the enzyme pocket residues. Initial work has revealed that novel core templates do have activity and moreover they are active in solid tumor cancer cell lines and potent against the malaria parasite (unpublished work).
Discovery of new H2S releasing compounds with improved anticancer activity
Hydrogen sulfide (H2S) has been shown to play significant roles in physiology and pathology. This requires appropriate H2S concentrations to be delivered at a suitable rate to exert a physiologic effect without overt toxicity. Organic H2S donors are able to release H2S slowly and continuously at concentrations similar to endogenous levels. The slow releasing H2S donor, GYY4137, has been found to show a concentration cell killing effect on seven different cancer cell lines (Zheng et al., PLoS ONE, 2011, 6, e21077). We are thus interested in synthesizing new H2S releasing compounds with a broad range of releasing profiles and identifying the best profiles for activity in cell lines. So far we have designed and synthesised a wide range of novel H2S donor molecules and established their in vitro H2S release profiles. In collaboration with leading biologists in the area, Prof Philip K Moore and Dr Lihwen Deng, a deeper understanding of the cellular biology and pharmacology of these compounds in inflammation and cancer is being determined, ultimately shedding light on the H2S working mechanism and potentially leading to a new generation of H2S donor drugs
Design and synthesis of kinesin inhibitors with potential anticancer applications
Cheng Shang: Kinesins are molecular motor proteins that utilize energy from ATP hydrolysis to travel along microtubules transporting a ‘cargo’ such as another protein. Kinesins play crucial roles in coordinating the various stages of the cell cycle (mitosis and cytokinesis), and hence are important targets in the fight against cancer. We are interested in synthesizing and testing kinesin inhibitors with broad potential as novel anticancer agents. Collaboration with Dr Sang Lee, Duke-NUS. We have discovered a novel dual acting anti-cancer agent that preferably kills cancer cells and not normal cells.
