Shelli McAlpine

Shelli McAlpine

Shelli McAlpine

Ph.D. (UCLA), 1997; Post-doc (Harvard University); FRACI

Associate Professor; Undergraduate Research Director

Contact details

Phone: +61 2 9385 4712


Room 219, Dalton Building
UNSW, Kensington, 2052

Research Group Website


Biographical Details

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.

Research Group Outputs

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.    

Research Interests

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 16 people (8 Ph.D.s, 3 honours students, and 5 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.

May 2016

Left to Right  

Back Row: Laura, Adrian, Dan, Yuqi, Mike, Shelli

Front Row: Nicole, Yao, Koay, Marwa, Jess, Sam

Left to Right : the Boys in their white shirts 

Yuqi, Mike, (Shelli), Adrian, and Dan


 (a)           Synthesis and mechanism studies of new heat shock protein inhibitors

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.  The clinic drugs (termed "classical inhibitors") bind to Hsp90 at the N-terminus 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 not only block the function of heat shock protein 90 (hsp90) but they also shut down the resistance mechanism, 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 effectivley leads to programmed cell death. 


Furthermore, 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. Desiging new and higly soluble analogs ofr mouse model and cancerous tissue studies is a project that is currently underway in our lab.



(b)           Synthesis of Heat shock protein 27 (Hsp27) inhibitors

HSP27 is an ATP-independent molecular chaperone, whose sequence is highly conserved compared to other HSPs. HSP27 contains a conserved α-crystallin domain, a highly flexible but conserved C-terminus, and a highly variable N-terminus. The protein typically exists as large polydisperse oligomers (sizes up to 800 kDa, 29-mers) with the average size being 14-mers. The size of the oligomers is dependent on multiple physicochemical parameters including temperature, pH and degree of protein phosphorylation.

 When subjected to physicochemical stress, HSP27 protein levels not only increase in order to facilitate folding the large number of proteins that require protein-folding and de-aggregation, but is also phosphorylated (see figure below). Recent work has shown that the phosphorylation of serines 15, 78, and 82, drives the equilibrium of oligomers to dimers.  The dimers are the active form of the protein, and are responsible for folding and de-aggregating proteins, that is, the chaperone activity.  For Parkinson’s, ALS and Alzheimer’s, driving the equilibrium to dimers to promote chaperone activity is optimal.  For cancer, trapping the monomer is optimal as it will have no chaperone activity and hence, proteins will aggregate in the cell, promoting apoptosis.  Thus, our work is focusing on generating molecules that inhibit the dimer and oligomer formation, whereby we trap the monomer and inhibit the aggregation back into the dimer.  This project involves synthesizing numerous inhibitors based on that are focused on specific regions of Hsp27 sequence.


(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 involves making  derivatives, and investigating the structure-activity relationships and their mechanism of action.  Inverting the stereochemistry on the peptide side chains is well established by our lab to impact the ring conformation and hence biological activity.  Thus, derivatives will focus on how modifying these side chains, both stereochemical and structural changes, impacts biological activity. Eavluaing the compounds in a series of appropriate biological assays will provide evidence of which compounds are the most effective.        



(d)           Synthesis of heat shock protein 70 (Hsp70) inhibitors- mimicking TPR1 domain

Cancer cells overexpress heat shock proteins (hsps), and specifically high levels of heat shock protein 70 (up to 10 fold) in order to facilitate their unrestrained growth. Indeed, cancer cells are dependent on Hsps for survival, and inhibition of Hsp90 or Hsp70 has proven toxic to cancer cells but not normal cells. This specific toxicity to cancer cells indicates that Hsp inhibitors could provide new, targeted cancer therapies, and recent success with both Hsp90 and Hsp70 inhibitors provides promising preliminary data.  Most studies have focused on Hsp90 inhibitors, and there are numerous clinical trials currently testing inhibitors. However, Hsp70 appears to be more critical than Hsp90 to the cell under stressed conditions, hence Hsp70 may be a highly effective chemotherapeutic target.

Hsp70 has a highly conserved structure consisting of a nucleotide-binding domain (NBD), which binds ATP and a substrate-binding domain (SBD), which binds the proteins that require Hsp70 chaperone function; both domains have been targeted as sites for inhibiting Hsp708. The interaction of Hsp70 with other proteins such as HOP (heat shock organizing protein) (see figure) is an opportunity to block the primary function of Hsp70.  By binding to Hsp70 and inhibiting it’s interaction with HOP, one can inhibit the protein folding process, and thereby induce large amounts of unfolded protein.  Once the cell is overwhelmed with unfolded protein it goes into apoptosis, or programed cell death.  Currently we are designing molecules that mimic the TPR1 site on HOP, with the goal that this mimic will bind to Hsp70 and block its ability to interact with HOP.  Work on this project will involve synthesizing molecules that mimic the TPR1 domain, focusing on the inclusion of specific residues that are critical for binding between Hsp70 and HOP.


e)           Synthesis of Heat Shock Protein 90 (Hsp90) inhibitors- mimicing the TPR2A domain

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.  In this project we are investigating whether these molecules inhibit Hsp90 interacting with HOP via a direct binding interaction with Hsp90.  Our lab has shown that designing molecules that target the MEEVD region is highly effective for blocking the interaction between Hsp90 and TPR-containing proteins like HOP.  This project involves synthesizing molecules that mimic the TPR domain, and with the goal of also produced cell permeable molecules.  Specifically, once the molecules are optimized for binding to the MEEVD region, masking groups are being placed on the polar side changes in order to allow the compounds to enter the cell , and then be revealed once in the cytosol.    


 (f)   Mechanism studies on heterocyclic fragments        

 Linked azoles are unique substructures that are present in many natural products (see figure). Over the past two decades there has been a surge in the discovery of natural product compounds that contain linked azoles and many of these compounds are now candidates for dug development. Urukthapelstatin A (Ustat A) is a natural product isolated from marine bacteria and it shows potent anticancer activity against a panel of human cancer cell lines, with an average IC50 value of 12 nM.22-24 This molecule has a unique bisoxazole and bisthiazole moiety located within the macrocycle. HXDV is a synthetic derivative of telomestatin, and it exhibits anti-proliferative and apoptotic activity by stabilizing the G-quadruplex, thereby inducing M-phase cell cycle arrest.25-26 It has two linked tri-oxazoles within its macrocyclic backbone. Marthiapeptide A is another potent natural product that contains a linked trithiazole-thiazoline system, and cytotoxicity with an IC50 = ~380-520 nM against a panel of cancer cell lines.

Inspired by the linked azoles observed within these three biologically active molecules and the activity of linked azole molecules we have previously reported, we designed a series of linked thiazoles and oxazoles with both R and S stereochemistry at the tail end of the molecule, since all 3 natural products have a substituent at this position. The top portion of the molecule required a capping agent, and we investigated three different moieties including ester, amide and thioamide. We found that thiazoles were the most effective at inhibiting cell growth, and inducing apoptosis, and had low µM GI50 values (versus oxazoles that had no effect).  Curently this project involves synthesizing thiazole analogs with modifications to the stereochemistry at the tail end of the compound, and the capping group.  Testing these compounds in biological assays could show that the ring structure is unnecessary to produce highly potent compounds.


Publications for the past 5 years

A complete list of Prof. McAlpine's publications is available here.
  ∞ = Invited and peer reviewed Book Chapter
  = these two authors contributed equally

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 In press 2016 

74.  Allosteric Modulators of Heat Shock Protein 90 (HSP90) Yen Chin Koay and Shelli R. McAlpine * In Press Royal Society of Chemistry: “Allosterism in Drug Discovery” 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

 70.  Synthesis of the natural product Marthiapeptide A Yuqi Zhang, Amirul Islam, and Shelli R. McAlpine* Org. Lett. V17, p5149-5151 2015

 69.  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 

68.  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  2015 

67. 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 2015
66.  Predicating the unpredictable: recent examples of biologically active heterocycle-containing macrocycles Hendra Wahyudi and Shelli R. McAlpine*  Bioorganic Chem. V60, 74-97  2015

65.  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 2015 

64.   Hsp47: The new heat shock protein therapeutic target George Sharbeen, Shelli R. McAlpine, Phoebe Phillips* In Press Springer Books: “Heat shock Proteins: Success Stories” DOI: 10.1007/7355_2015_89, 2015

63.   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.  2015

62.  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  2015

61.  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  2015
60.  C-terminal heat shock protein 90 modulators produce desirable oncogenic properties Yao Wang and Shelli R. McAlpine* Org. Biomol. Chem:V13, 4627-4631   2015
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 2015

58. Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Yao Wang, and Shelli R. McAlpine*  Org. and Biomol. Chem.  V13, P2108-2116 2015
57. 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, 2015

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

51. Chemically accessible hsp90 inhibitor that does not induce a heat shock response.  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
 ∞ 49. Recent Advances in Macrocyclic Hsp90 Inhibitors Deborah Ramsey, R.R. A Kitson, J. I Levin, C. J Moody*, and S. R. McAlpine*  Book Chapter accepted by RSC Book Titled: Macrocycles in Drug Discovery ,  10.1039/9781782623113-00037; p37-77 2014
48. A Heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing a heat shock response Jeanette R. McConnell, Leslie D. Alexander, and Shelli R. McAlpine* Bioorg. & Med. Chem Lett. V24, p661-666 2014
47. Utilizing a Dimerization strategy to inhibit the dimer protein Hsp90:  Synthesis and biological activity of a sansalvamide A dimer Hendra Wahyudi, Yao Wang, and Shelli R. McAlpine* Org. and Biomol. Chem. V12, p765-773 2014 
46. Total synthesis and biological activity of the natural product Urukthapelstatin A  Chun Chieh Lin, Worawan Tantisantisom, and Shelli R. McAlpine* Org Lett.  V15, p3574-3577, 2013
45. Mechanism of action for a novel macrocycle: a small molecule inhibitor of the ribosome machinery Worawan Tantisantisom, Deborah M. Ramsey, and Shelli R. McAlpine*  Org. Lett.   V15, p4638-4641,  2013
 44. Effectively delivering a drug using star polymers: Improving solubility of a unique hsp90 inhibitor Seong Jong Kim, Deborah M. Ramsey, Cyrille Boyer, Thomas Davis, and Shelli R. McAlpine*  ACS Med. Chem. Lett. V4, p915-920,  2013
43. Novel Marine Natural Products that target the gram-positive Cell Wall Deborah M. Ramsey,* Amirul Islam, Rohan A. Davis, Cynthia B. Whitchurch, Lynne Turnbull  and Shelli R. McAlpine Bioorg. & Med. Chem Lett.  V23, p4862-4866, 2013
42. A potential Rhodium Cancer Therapy: studies of a cytotoxic organorhodium Jeanette R. McConnell, Dimple P. Rananaware, Deborah M. Ramsey, Kai N. Buys, 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, 2013
40. 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  2013
39. 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, 2013
38. Halting Metastasis through CXCR4 inhibition Deborah M. Ramsey* and Shelli R. McAlpine*  Bioorg. & Med. Chem. Lett. V23, p20-25, 2013
37.    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, 2012
36. 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, 2012
35. 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 Lettersv53, p4065-4069, 2012
34.    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, 2012
33.    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*  Tetrahedronv68, p1029-1051, 2012
32.    Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteinsVeronica C Ardi, Leslie D. Alexander, Victoria Johnson, and Shelli R. McAlpine* ACS Chemical Biology v6, p1357, 2011
31. Small Molecule Inhibitors of Hsp90’s Conformational Changes Leslie D. Alexander, James Partridge, David Agard, and Shelli R. McAlpine*  Bioorganic and Med. Chem. Lett.v21, p7068-7071, 2011
30. Synthesis and Evaluation of Biotinylated Sansalvamide A Analogs and their modulation of Hsp90 Joseph Kunicki, Mark Petersen, Leslie D. Alexander, Veronica C. Ardi, Jeanette McConnell, and Shelli R. McAlpine* Bioorganic and Med. Chem. Lett, v21, p4716-4719, 2011