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
Email: s.mcalpine@unsw.edu.au

Office

Room 219, Dalton Building
UNSW, Kensington, 2052

Research Group Website

/research/research-groups/mcalpine-group

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 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 12 people (10 post-grads, two honours students, and a post-doc). 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.

Mcalpinegroup22014

April 2014

Left to Right  Back Row: Eric, Hendra, Adrian, Yuqi, Amirul Seong Jong, Shelli

Front Row: Precilia, Yao, Koay, Marwa, Cara, 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.

 

Research Group Outputs

Our research group typically publishes 5-10 papers per year. We vary in size between 10-15 people, including a post-doc, 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.    

Selected Publications

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

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*  In press ACS Med. Chem Lett.  2014      http://dx.doi.org/10.1021/ml500114p                 
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 
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 Letters, v53, 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*  Tetrahedron, v68, 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
29.  A third generation of Sansalvamide A derivatives: Design and synthesis of Hsp90 inhibitors Robert P. Sellers, Leslie D. Alexander, Victoria A. Johnson, Chun-Chieh Lin, Jeremiah Savage,  Ricardo Corral, Jason Moss, Tim S. Slugocki, Erinprit K. Singh, Melinda R. Davis, Suchitra Ravula,  Jamie E. Spicer, Jenna L Oelrich, AndreaThornquist, Chung-Mao Pan, and Shelli R. McAlpine*  Bioorganic Med. Chem.  v18, p6822-6856 2010
28. Histone deactylace inhibitors: Synthesis of cyclic tetrapeptides & their triazole analogs Erinprit K. Singh, Lidia A. Nazarova, Stephanie A. Lapera, Leslie D. Alexander and Shelli R. McAlpine* Tetrahedron Letters v51, p4357-4360 2010
27.  Macrocyclic inhibitors of Hsp90 Victoria A. Johnson, Erinprit K. Singh,  Lidia A. Nazarova, Leslie D. Alexander, and Shelli R. McAlpine*  Current Topics in Medicinal Chemistry v23, p1380-1402 2010
26. Mechanistic studies of Sansalvamide A-amide:An allosteric modulator of Hsp90 Robert C. Vasko, Rodrigo A. Rodriguez, Christian Cunningham, Veronica Ardi, David Agard, and Shelli R. McAlpine*   ACS  Medicinal Chemistry Letters v1, p4-8  2010