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.
We vary in size between 8-12 people, including 6-8 post-graduate students, 2-3 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.
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 11 people (6 Ph.D.s, 1 Msc, 1 honours students, and 3 undergraduates). 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: Mike, Adrian, Yuqi, Leo, Jena, Shelli
Front Row: Yuantao, Gabe, Laura, Marwa, Sam, Jess
OVERVIEW OF HEAT SHOCK PROTEINS
Heat shock proteins are in charge of folding and maintaining over 400 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 can induce cell death. There are molecules targeting individual heat shock proteins, where the most advanced are those targeting Heat shock protein 90 (Hsp90). Clinic drugs (termed "classical inhibitors") that bind to Hsp90 target the N-terminus of the protein and block ATP from binding to hsp90,thereby inhibiting protein folding. Our data show that these clinic/classical drugs are not only highly promiscious, but they also produce a massive rescue response in the cell called the heat shock response. Thus, their ability to kill cells is limited and has lead to clinical failures, where initially 15 drugs targeted the ATP binding site of Hsp90, and only 3 are left in the clinic. In contrast, our SMX inhibitors, which act through an allosteric mechanism, not only blocks the function of heat shock protein 90 (hsp90) but they also shut down the resistance mechanism,or the heat shock response. By binding to hsp90 and controlling its C-terminus, the SMX molecules halt protein folding by blocking binding betwee HOP and Hsp90. This prevents the transfer of the unfolded protein between Hsp70 and Hsp90, and thus it inhibits Hsp90's role in folding. With Hsp90 no longer folding proteins, large amounts of unfolded protein are produced, which effectively leads to programmed cell death.
The SMX inbhitors induce high levels of cell death in cancer cells over normal cells, showing a 3 fold selectivity, while the clinic drug does not. All of these positive outcomes are likely related to the fact that SMX inhibitors modulate the C-terminus, while the clinic/classical drugs control ATP from binding to Hsp90 during the folding cycle.
(a) Designing Heat shock protein 27 (Hsp27) inhibitors
Many diseases are the result of an imbalance between proteins being produced, folded, and degraded. Alzheimer’s and Parkinson’s result from improperly folded or aggregate proteins; facilitating the folding of aggregates may successfully treat these diseases. Cancer relies on cells to be highly efficient at folding proteins; inhibiting the folding process may successfully treat malignancy. Heat shock protein 27 (Hsp27), a small chaperone, initiates protein-folding events and its inadequate or excessive function is connected to diseases such as Alzheimer’s and cancer respectively. Developing a molecule that controls Hsp27’s function by switching protein folding on or off would afford fundamental new knowledge about critical protein folding processes and shed light on these diseases.
It is our hypothesis that molecules designed from specific regions of Hsp27 can be used to modulate Hsp27’s protein folding activity. These molecular switches will provide fundamental new knowledge on protein folding processes, and shed light on the role of Hsp27 in multiple disease states.
Why target Hsp27: Folding new or dysfunctional proteins involves proteins called chaperones. Although there are several important chaperones, Hsp27 is perhaps one of the most important because defects in this protein are directly linked with many neuronal diseases. Yet as a pro-survival protein, high levels of Hsp27 are associated with malignant progression in multiple cancers. Thus, disregulation of Hsp27 appears to control many disease states.
Hsp27: When not functioning as a chaperone, Hsp27 exists as large oligomers, up to sizes of 800 kDa (30-mers), with the average size of 590 kDa (~24-mers). In order to perform its chaperone activity and prepare proteins for folding, Hsp27 must be disassembled into dimers, which are typically observed by a decrease in average oligomer size (~300 kDa, 14-mers). Oligomeric Hsp27 assembles using velcro-like connections between the bound subunits. Disassembling into active dimers means the connections between the protein subunits must uncouple for release. Establishing which regions within Hsp27 facilitate protein folding versus which regions deactivate the chaperone activity is still at the early stages of investigation.
Current status: We are currently designing molecules that bind to Hsp27 with the goal of regulating whether the molecules are oligomers or dimers. Via several collaborations, with Mass Spectroscopist Dr. Alex Donald (UNSW) and Hsp27 biology expert A/Prof Heath Ecroyd we are determining how to design the most effective Hsp27 regulators.
(b) Designing heat shock protein 70 (Hsp70) inhibitors
A molecule that can selectively kill cancer cells and not impact normal cells would be of tremendous therapeutic interest. Targeting a protein involved in rapid cell division is one approach likely to achieve this selectivity. One such protein, heat shock protein 70 (Hsp70), controls protein folding events that are required for rapid cell division. Molecules that could control Hsp70’s role in protein folding would provide fundamental new knowledge about critical protein folding processes, which may lead to new discoveries for selectively targeting cancer cells.
Why target protein folding events: Cells require a litany of proteins to run their internal machinery. All proteins are produced as linear amino acid sequences, which are initially inactive. These linear sequences must be folded into the correct conformation before they can perform their cellular role. In order to maintain their rapid growth, cancer cells produce significantly more proteins, which require folding, than normal cells. In contrast, normal cells, which grow slowly, have a minimal need for making new proteins instead they rely on proteins already present to maintain their function. Thus, blocking protein folding events would dramatically impact cancer cells but would have a low impact on normal cells.
Why Hsp70: Folding new proteins into their active conformation so that they can function involves proteins called chaperones. Although there are several important chaperones involved in protein folding, one of the major chaperones is heat shock protein 70 (Hsp70). Together with several other co-chaperones, Hsp70 facilitates the folding of most oncogenic proteins in the cancer cell machinery. By folding these proteins into an active conformation, Hsp70 is enabling cancer cells to reproduce. Hsp70 is potentially the most important chaperone for cancer cells as it is the only chaperone produced at levels of up to 1000 times higher concentration in most cancer cells over most normal cells. The high levels of Hsp70 in cancer compared to normal cells indicates that blocking Hsp70 function will selectively impact cancer over normal cell growth.
Current status: We are currently designing molecules that bind to Hsp70 and block its interaction with the co-chaperone HOP. Blocking HOP from binding to Hsp70 should inhibit protein folding and produce cell death.
(c) Synthesis of Heat Shock Protein 90 (Hsp90) inhibitors
Heat shock protein 90 (Hsp90) is a chaperone that regulates the highly complex protein folding machinery and it is responsible for folding and stabilizing over 400 proteins, including many that support malignancy. Hsp90 plays an important role in cancer, where it makes up 4-5% of all protein in cancer cells but only 1-2% in normal cells. The timing and types of proteins being folded by Hsp90 are dictated by co-chaperones that bind to Hsp90’s C-terminus. Molecules that block binding between Hsp90 and these C-terminal binding co-chaperones would inhibit Hsp90’s protein folding function, induce degradation, and provide new opportunities for chemotherapeutics.
It is our hypothesis that a molecule blocking the interaction between Hsp90 and C-terminal-binding co-chaperones will be highly effective at regulating protein folding and inducing rapid cell death. Producing a molecule that controls proteostasis via Hsp90 will provide lead structures for chemotherapeutic development. These new structures will select for cancer over normal cells because they will regulate a mechanism that is critical to malignancy.
Why target Hsp90? In the family of chaperones, there are several that play key roles in proteostasis to maintain cancer cell growth. However, Hsp90 is considered the driver of the protein folding machinery, where the concentration of Hsp90 is 200-300% in cancer cells over that in normal cells. Hsp90 and co-chaperones that bind to Hsp90’s C-terminus control over 400 proteins (clients) and dictate whether they are folded, stabilized, or degraded. Many of these clients promote cancer cell growth, including: receptor tyrosine kinases, serine/threonine kinases, steroid hormone receptors, p53, Raf-1, CDK4, Her-2, HIF1a, MMP2, Teleomerase. By facilitating folding or degradation of these oncogenic proteins, Hsp90 enables cancer cell growth. Thus, blocking access between Hsp90 and the co-chaperones that regulate these folding events would change the proteostasis balance to favour unfolded proteins, and ultimately cell death.
Why examine the interaction between Hsp90 and C-terminal co-chaperones? Hsp90 has three structural domains, the amino (N) –terminal domain, the middle (M)-domain, and the carboxy (C) –terminal domain. ATP binds to the N-domain, and most of Hsp90’s clients bind to the M-domain. The C-terminal domain is responsible for mediating interactions with co-chaperones, where these interactions drive the protein folding process and control which proteins are folded or degraded. Thus, blocking the interaction between Hsp90 and the C-terminal binding co-chaperones will ensure the entire protein folding machinery is shut down. The C-terminus of Hsp90 contains acidic residues, which bind to basic residues located within the nine co-chaperones that regulate protein folding events.
Current status: We are currently designing molecules that bind directly to the C-terminus of Hsp90, several block interactions between Hsp90 and co-chaperones. We are also ensuring they are cell permeablility and investigating our new direct inhibitor's mechanism of action.
here. ∞ = Invited and peer reviewed Book Chapter ‡ = these two authors contributed equally
79. Rita mimics: synthesis and mechanistic evaluation of asymmetric linked trithiazoles. Adrian Pietkiewicz‡, Yuqi Zhang‡, Marwa N. Rahimi, Michael Stramandinoli, Matthew Teusner, and Shelli R. McAlpine* ACS Med. Chem. Lett. in press. DOI: 10.1021/acsmedchemlett.6b00488 2017
78. Redefining the phenotype of heat shock protein 90 (Hsp90) inhibitors. Yao Wang, Yen Chin Koay, and Shelli R. McAlpine* Chem. Eur. J.. in press. 10.1002/chem.201604807 2017
77. How selective are Hsp90 inhibitors for cancer cells over normal cells? Yao Wang, Yen Chin Koay, and Shelli R. McAlpine* ChemMedChem. in press. 10.1002/cmdc.201600595 2017
76. Reininventing Hsp90 inhibitors: Blocking C-terminal binding events to Hsp90 using dimerized inhibitors. Yen Chin Koay, Hendra Wahyudi, and Shelli R. McAlpine* Chem. Eur. J. V22, p18572-18582 2016
75. A novel class of Hsp90 C-terminal modulators have preclinical efficacy in prostate tumor cells without induction of a heat shock response Heather K. Armstrong, Yen Chin Koay, Swati Irani, Rajdeep Das, Zeyad D. Nassar, The Australian Prostate Cancer BioResource, Luke A. Seth, Margaret M. Centenera, Shelli R. McAlpine* and Lisa M. Butler* The Prostate, V76, p1546-1559 2016
∞74. Allosteric Modulators of Heat Shock Protein 90 (HSP90) Yen Chin Koay and Shelli R. McAlpine * RSC Drug discovery series: “Allosterism in Drug Discovery” DOI: 10.1039/9781782629276, p404-426 2016
73. Hydrothermal synthesis of highly luminescent blue-emitting ZnSe(S) quantum dots exhibiting low toxicity Fatemeh Mimajafizadeh, Deborah Ramsey, Shelli R. McAlpine, Fan Wang, Peter Reeece, and John Arron Stride*, Mat. Science and Eng. C V.64, p167-172 2016
72. Hitting a moving target: How does an N-Methyl group impact biological activity? Yen Chin Koay, Nicole L. Richardson, Samantha S. Zaiter, Jessica Kho, Sheena Y.Nguyen, Daniel H. Tran, Ka Wai Lee, Laura K. Buckton, and Shelli R. McAlpine* ChemMedChem. V11, p881-892 2016
71. The first report of direct inhibitors that target the C-terminus MEEVD region on heat shock protein 90 Laura K. Buckton, Hendra Wahyudi, and Shelli R. McAlpine* Chem. Commun. V52, p501-504 2016
∞69. Are some Hsp90 therapies more effective than others? Evaluating dual Hsp90 and Hsp70 inhibition as an anticancer therapy Laura K Buckton, Yao Wang, Jeanette R. McConnell, and Shelli R. McAlpine* In Press Springer Books: “Heat shock Proteins: Success Stories” DOI: 10.1007/7355_2015_96. 2016
∞68. Heat shock protein 27: structure, function, cellular Role and inhibitors Rashid Mehmood* and Shelli R. McAlpine* In Press Springer Books: “Heat shock Proteins: Success Stories” DOI: 10.1007/7355_2015_94 2016∞67. Targeting the c-terminus of heat shock protein 90 as a cancer therapy Jeanette R McConnell, Yao Wang, Shelli R. McAlpine* In Press Springer Books: “Heat shock Proteins: Success Stories” DOI: 10.1007/7355_2015_93 201666. Synthesis of the natural product Marthiapeptide A Yuqi Zhang, Amirul Islam, and Shelli R. McAlpine* Org. Lett. V17, p5149-5151 2015
65. Blocking the heat shock response and depleting HSF-1 levels through heat shock protein 90 (hsp90) inhibition: A significant advance over current chemotherapies Yen Chin Koay, Jeanette R. McConnell, Yao Wang, and Shelli R. McAlpine* RSC Advances V5, 59003-59013 2015
64. Regulating the master regulator: controlling heat shock factor-1 as a chemotherapeutic Jeanette R. McConnell, Laura K Buckton, and Shelli R. McAlpine* Bioorg. Med. Chem Lett. V25, 3409-3414 201563. Thioimidazoline based compounds reverse glucocorticoid resistance in acute lymphoblastic leukemia cells Cara Toscan, Marwa Rahimi, Mohan Bhadbhade, Russell Pickford, Shelli R. McAlpine* and Richard Lock* Org. Biomol. Chem. V13, 6299-6312 201562. Predicating the unpredictable: recent examples of biologically active heterocycle-containing macrocycles Hendra Wahyudi and Shelli R. McAlpine* Bioorganic Chem. V60, 74-97 2015
61. Activation of the Nuclear Factor kB inducing kinase inducing kinase as a mechanism of beta cell failure in obesity Elisabeth K. Malle, Nathan W. Zammit, Stacey N. Walters, Yen Chin Koay, Jianmin, Wu, Bernice, M. Tan, Jeanette E. Villanueva, Robert Brink, Tom Loudovaris, James Cantley, Shelli R. McAlpine, Daniel Hesselson, Shane T. Grey* J. Exp. Med. V212, 1239-1254 201560. C-terminal heat shock protein 90 modulators produce desirable oncogenic properties Yao Wang and Shelli R. McAlpine* Org. Biomol. Chem:V13, 4627-4631 2015ON THE COVER OF ORG. BIOMOL. CHEM.59. Combining an Hsp70 inhibitor with either an N-terminal and C-terminal hsp90 inhibitor produces mechanistically distinct phenotypes Yao Wang and Shelli R. McAlpine* Org. Biomol. Chem. V13, 3691 201558. Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Yao Wang, and Shelli R. McAlpine* 2015 Org. and Biomol. Chem. V13, P2108-2116 201557. Design, synthesis and anticancer activity of linked azoles Amirul Islam, Yuqi Zhang, Yao Wang, and Shelli R. McAlpine* Med. Chem. Comm. V6, P300-305 2015 56. Heat Shock Protein 90 inhibitors: will they ever succeed as chemotherapuetics? Yao Wang, and Shelli R. McAlpine* Future Medicinal Chemistry V7 V2, p87-90 2015 55. The fungal natural product (1S, 3S)-austrocortirubin induces DNA damage via a mechanism unique from other DNA damaging agents Yao Wang ‡, Amirul Islam ‡, Rohan Davis, and Shelli R. McAlpine* Bioorg. & Med. Chem. Comm. V25, 249-253 2015 54. N-terminal and C-terminal moduation of hsp90 produce dissimilar phenotypes. Yao Wang and Shelli R. McAlpine* Chem Comm. V51, 1410-1413, 2015ON THE COVER OF CHEM COMM
53. HSP90 inhibitors and conjunctival melanoma M Madigan, X. Quah, S. McAlpine, and R. M. Conway, Acta Ophthalmologica, V92, S253, 2014 52. Synthesis of macrocycles that inhibit protein synthesis: stereochemistry and structural based studies on sanguinamide B derivatives Adrian L. Pietkiewicz, Hendra Wahyudi, Jeanette R. McConnell and Shelli R. McAlpine* Tetrahedron Lett. V55, 6979-6982 2014 ON THE COVER OF TETRAHEDRON LETTERS
Yen Chin Koay, Jeanette R McConnell, Yao Wang, Seong Jong Kim, Laura Buckton, Flora Mansour and Shelli R. McAlpine* ACS Med. Chem Lett. V5, p771-776 2014 50. Synthesis and Cytotoxicity of sanguinamide B analogs: identification of an active macrocyclic conformation. Hendra Wahyudi, Worawan Tantisantisom and Shelli R. McAlpine* Tetrahedron Lett. V55, P2389-2393 2014 ON THE COVER OF TETRAHEDRON LETTERS Marcus L. Cole & Shelli R. McAlpine* Bioorg. & Med. Chem Lett. V23, p2527-2531 2013 41. Heat shock proteins 27, 40, and 70 as combinational therapeutic targets Jeanette R. McConnell and Shelli R. McAlpine* Bioorg. & Med. Chem Lett.V23, p1923-1928, 201340. An efficient synthetic route for synthesizing macrocycles that contain heterocycles: Solid Phase versus Solution Phase Synthesis Seong Jong Kim and Shelli R. McAlpine* Molecules V18 p1111-1121 201339. A structure-activity relationship study on multi-heterocyclicmolecules: two linkedthiazoles are required for cytotoxic activity Seong Jong Kim, Chun Chieh Lin, Chung-Mao Pan, Dimple P. Rananaware, Deborah M. Ramsey, and Shelli R. McAlpine* Med. Chem. Comm. V4 , p406-410, 201338. Halting Metastasis through CXCR4 inhibition Deborah M. Ramsey* and Shelli R. McAlpine* Bioorg. & Med. Chem. Lett. V23, p20-25, 201337. Synthesis, structure-activity analysis, and biological evaluation of structurally related conformational isomers Hendra Wahyudi, Worawan Tantisantisom, Xuechao Liu, Deborah M. Ramsey, Erinprit K. Singh, and Shelli R. McAlpine* J. Org. Chem. v77, p10596-10616, 201236. A new Hsp90 inhibitor that exhibits a novel biological profile Deborah M. Ramsey, Jeanette R. McConnell, Leslie D. Alexander, Kaishin W.Tanaka, Chester M. Vera, and Shelli R. McAlpine* Bioorg. and Med. Chem. Lett. v22, p3287-3290, 201235. Progress towards the synthesis of Urukthapelstatin A and two analogs Chung-Mao Pan, Chun-Chieh Lin, Seong Jong Kim, Robert P. Sellers, and Shelli R. McAlpine* Tetrahedron Letters, v53, p4065-4069, 201234. Total Synthesis of Natural Product trans,trans- Sanguinamide B and its structurally related conformational isomersErinprit K. Singh, Deborah M. Ramsey, and Shelli R. McAlpine* Org. Lett. v14, p1198-1201, 201233. Synthesis of Sansalvamide A Peptidomimetics: Triazole Oxazole, Thiazole, and Pseudoproline containing compounds Melinda R. Davis, Erinprit K. Singh, Hendra Wahyudi, Leslie D. Alexander, Joseph Kunicki, Lidia A. Nazarova, Kelly A. Fairweather, Andrew Giltrap, Katrina A. Jolliffe, and Shelli R. McAlpine* Tetrahedron, v68, p1029-1051, 2012