Ph.D. (UCLA), 1997; Post-doc (Harvard University); FRACI
Associate Professor; Undergraduate Research Director
Phone: +61 2 9385 4712
Room 219, Dalton Building
UNSW, Kensington, 2052
Research Group Website
1987-1991 B.S. University of Illinois Champaign/Urbana. Research with Prof. Eric N. Jacobsen; 1991-1993 Research Associate Merck Pharmaceuticals; 1993-1997 Ph.D. UCLA Organic chemistry; 1997-2000 Post-doc at Harvard University with Professor Stuart Schreiber; 2000-2006 Assistant Professor at San Diego State University; 2006-2010 Associate Professor at San Diego State University; 2010-2011 Professor at San Diego State University; 2011-current Associate Professor at UNSW.
In 2011 I moved my research lab from San Diego State University (SDSU) to the University of New South Wales (UNSW). Our lab currently consists of 13 people (10 post-grads, two honours students, and an undergraduate). We work on a diverse array of projects involving organic synthesis, molecular and cancer biology, and biochemistry. Our synthesis projects start from a natural product template, and our goal is to design analogues of the natural product. We then test these molecules in cell growth assays, biochemical assays, and cell-based assays in order to determine their activity and potency. Once we understand their biological target, we then design new analogues to improve their selectivity, solubility and efficiency.
Left to Right
Back Row: Adrian, Amirul, Yuqi, Seong Jong, Hendra, Cara, Shelli
Front Row: Nicole, Yao, Koay, Marwa, Zohreh, Laura, Jeanette
(a) Synthesis and mechanism studies of new heat shock protein inhibitors
Heat shock proteins are in charge of folding and maintaining over 200 other proteins in the cell. They are essential for protecting these proteins from stress-related damage. In cancer cells these proteins are up-regulated and they protect the cells from dying. Blocking the function of heat shock proteins induces cell death. SM145 not only blocks the function of heat shock protein 90 (hsp90) but it also avoids the current resistance mechanism associated with hsp90 inhibitors in the clinic (see the figure below). By binding to hsp90, SM145 halts the maturation of the hormone receptors, does not induce a heat shock response, and inhibits all co-chaperones and proteins from binding to the C-terminus of hsp90. We are currently optimizing SM145’s structure for mice model and pK studies.
(b) Synthesis of novel ribosomal inhibitors: Sanguinamide B
Sanguinamide B (San B) is unique natural product that was isolated from a sea slug. We have made a number of derivatives of this natural product and found that it targets the ribosome, where proteins are made. Protein synthesis is critical for cells to survive, thus, inhibiting this process is one good mechanism to stop cancer cells from growing. This project involves the synthesis of new derivatives that optimize the macrocycles’s ribosomal binding activity and most effectively inhibit protein synthesis. We will then evaluate which San B derivatives are the best lead structures to move forward into additional model systems.
(c) Synthesis and mechanism studies of Marthiapeptide A
Marthiapeptide A is a natural product that is extremely potent at inhibiting cancer cell growth (nanomolar potency). Our goal is to synthesize and investigate its potential as an anti-cancer therapy. We have developed a successful route for making the natural product. This project would involve making several derivatives, and investigating their mechanism of action. Experimental techniques will include synthetic organic chemistry, NMR, LCMS, DNA binding assays, cell growth and death assays, and perhaps other new assays based on the biological results.
(d) Synthesis and mechanism studies of Urukthapelstatin A
Urukthapelstatin A (Ustat A) is a natural product that has shown extremely potent activity at inhibiting cell growth (low nM). We have published the total synthesis of this compound, and are now making analogs in order to evaluate the structure activity relationship in cancer cell growth assays. In addition, we are running mechanism studies with the natural product in order to determine the specific oncogenic pathway being disrupted by Ustat A.
(e) Studying heat shock protein 90 inhibitors that deplete heat shock proteins
Clinical molecules, such as 17-AAG, target heat shock protein 90 (hsp90) at the N-terminal site, this binding event induces a cell protection and resistance mechanism. Both the cell protection and resistance mechanisms rely on increased levels of three heat shock proteins: hsp70, hsp40, and hsp27, all of which are increased with clinical inhibitors. In contrast to clinical inhibitors the molecules we have generated in our lab, including SM122 and SM145 decrease these protein levels. This project involves studying why our molecules are so effective at blocking the cell protection and resistance mechanisms and inducing cancer cell death compared to clinical compounds.
f) Synthesis of new anticancer agents that mimic the TPR domain of HOP
Heat shock proteins are in charge of folding and maintaining over 400 proteins in the cell. Blocking heat shock protein 90’s (Hsp90’s) ability to fold these proteins in cancer cells damages the cells, and pushes the cells into programmed cell death. This project involves synthesizing molecules that mimic the TPR2A domain on the protein HOP, called TPR mimics. You would investigate whether these molecules inhibit Hsp90 interacting with HOP, and how this impacts protein folding and cancer cell growth. In this project you will learn organic synthesis, and biochemical and cell based assays.
(g) Mechanism studies of heterocyclic fragments
Cancer cells migrate to various sites in the body in a process called metastasis, and metastasis involves several pathways that are regulated by several mechanisms, including molecular chaperone Hsp90. We are investigating how SM145, Ustat A, San B derivatives and small heterocyclic fragments induce apoptosis in cancer cells. We use state of the art microscopes available at the UNSW BMSF facility to generate images such as these shown below, which are cancer cells treated with two different heterocyclic fragments.
(h) Synthesis and mechanism studies using nanoparticles
We have developed several unique inhibitors of heat shock protein 90 (hsp90), and specifically SM145 is extremely effective at inhibiting hsp90 and blocking the subsequent downstream effects of this major oncogenic chaperone. However, it is relatively hydrophobic and its limiting factor as a therapeutic is solubility. We are investigating several options for improving the solubility of SM145 without loosing its effectiveness. One such approach is to attach the compound to a polymer that will deliver the compound into the cell and then release it. We have successfully demonstrated that we can do this effectively. In the images below the yellow arrows show that both SM145 and the polymer-delivered SM145 induce DNA condensation and cell death via apoptosis. However the polymer-delivered compound does this much more effectively (~5 fold lower concentrations of drug). Development of effective polymers for mice models studies, coupled with new analogs of SM145 generated by our lab will provide the optimal compound for studying hsp90 inhibition.
Our research group typically publishes 5-10 papers per year. We vary in size between 10-15 people, including 8-10 post-graduate students, 1-2 honours students, and several undergraduates. Our creative and supportive environment brings out the best in students, and my students typically perform well on their final thesis. Not only do our students produce 5-10 papers throughout their post-graduate career, former members get jobs in both industry and academia. Given our interdisplinary group, each member learns about biological and synthetic aspects of their project. Students have the option to do both chemistry and biology using a combination of skills in both fields in order to complete the entire project. Having trained in the United States, I have significant contacts with other academics and industrial positions and can place my students in desirable jobs throughout Australia and the U.S.here. ∞ = Invited and peer reviewed Book Chapter ‡ = these two authors contributed equally