School of Chemistry, UNSW

Shelli McAlpine

Ph.D. (UCLA), 1997
Associate Professor
E-mail: s.mcalpine@unsw.edu.au
Research Group web site: http://www.chem.unsw.edu.au/research/groups/mcalpine/

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

I recently moved my research lab from San Diego State University (SDSU) to the University of New South Wales (UNSW). Our lab currently consists of 9 people at UNSW (1 honours student, 7 post-grads, and a post-doc). We have just completed our transition from SDSU to UNSW, and now all of our projects are located at UNSW.

Being an established Associate Professor, I have developed a fully-fledged research program in organic synthesis, and have initiated biological assays on the compounds we synthesize. We currently have 4 organic synthesis projects and 3 biology projects. Thus, we are looking for both synthetic chemists and biology students to do research in our group. The synthesis in our group ranges from making peptidomimetics using click chemistry to utilizing the Hantsch reaction and oxazole forming reactions for the synthesis of complex natural products. Once synthesized, our group members run our compounds in biological assays ranging from basic cytotoxicity assays using up to cancer cell lines (including colon, pancreatic, breast, and prostate), to mechanistic assays involving apoptosis, pull-down, RNAi, and protein binding assays. Thus, our group offers students the unique opportunity to do synthetic chemistry, biochemistry, and/or biology.

Our organic chemistry projects focus on synthesizing derivatives of macrocyclic natural products, which make excellent synthetic starting points for developing new drugs. By making derivatives, we establish structure-activity relationships (SAR) between the molecules and their biological target. These natural products are viable drug candidates, and their potency in numerous therapeutic areas has long been established. There are currently 720 peptides that are drugs on the market or in some stage of clinical trials, and they are successfully used in the therapeutic areas of antibiotics, immunosuppressants, and as anticancer agents. Shown below are the structures of the natural products that are being used as templates for derivatives made in our lab. One of the compounds, Sansalvamide A (San A) was recently shown by our group to inhibit a very important cancer regulating protein: Hsp90. Hsp90 is a heat shock protein that regulates a number of oncogenic (growth inducing) client proteins. Thus, by targeting Hsp90, San A and derivatives inhibit these client proteins from binding, which leads to their degradation, and ultimately causing the cell to die. Thus, our San A derivatives are excellent potential anti-cancer agents, as they induce cell death at least through this mechanism, and perhaps others. We are currently exploring San A's mechanism of action and the Hsp90 client proteins affected by San A's binding, as well as initiating mice toxicity studies. We have utilized Autodock to determine the specific interactions that Hsp90 makes with the San A structure, thus allowing us to design additional new potent molecules. Finally, we are making peptidomimetics in order to explore additional related structures that may have improved potency and stability in vivo. In addition to the San A project, we are taking the same medicinal chemistry approach to the other structures, where we synthesize derivatives, run cytotoxicity assays to assess their toxicity, run pull-down assays to find the proteins that interact with these molecules in the cells, and run biochemical binding assays and western blots to evaluate their specific effects on these proteins.

Other synthetic projects include the synthesis of Urukthapelstatin A analogs, and Sanguinamide B derivatives. In addition, we are currently working on a collaborative project with Prof Martina Stenzel that involves coupling our San A analogs to nanoparticles to improve their pharmacokinetic properties.

Drug Delivery project in collaboration with Prof. Martina Stenzel (Chem Eng)

Biology projects include defining the mechanism of action of our Hsp90 inhibitors, and discovering Hsp70 and Hsp47 inhibitors. In order to understand how our small molecules work both in biochemical and cell based assays, we utilize flow cytometry and the imaging facilities available at UNSW. This allows us to see the effects induced by our compounds.

Imaging of Hsp90 inhibitors using the Imaging Facilities at UNSW (with Renee Whan)

In addition, we have several collaborative projects in biology, one includes working with A/Prof Marcus Cole on biologically active metal complexes, and exploring their mechanism of action. Another involves screening natural product libraries from Dr. Rohan Davis at Eskitis, whereupon we found a compound with activity that is as effective as Vancomycin against gram +ve bacteria. Exploring their mechanism of action using techniques such as 2-D gels, imaging, and pull-down assays are the next step in this project.

Via my developed research program we maintain publishing at a reasonable frequency, and I expect each student to publish one paper/year on their project. Thus, the community knows our work, which helps my students find jobs and find post-doc positions. Among my most recent students to graduate, one student has twelve publications, another has seven publications, while eight others have graduated with between 2 and 5 publications. Indeed, I expect Ph.D. students to graduate with a minimum of five papers. Thus, we are a relatively productive group. In addition, we raise money to fund our research and travel to meetings. We have close ties to a number of biotechnology companies, including Johnson and Johnson, Neurocrine, Celgene, Vertex, Illumina, and Ligand. My students have been very successful in obtaining positions in a multitude of places (see "past members" page).

Because we have a diverse research program that ranges from synthesizing compounds to running biological assays, we encourage all students with interests ranging from organic synthesis to biology to explore the diversity of our projects and recognize the skills you will develop in our research group. Thus, we are interested in recruiting both synthetically oriented students as well as biology students. Please contact me if you are interested in learning more about our work.

SELECTED PUBLICATIONS

A complete list of Prof. McAlpine's publications is available here.

37. 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* In press Bioorganic and Med. Chem. Lett. (accepted Feb 22, 2012)

36. 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* In press Tetrahedron Letters (accepted Feb 24, 2012)

35. Total Synthesis of Natural Product trans,trans- Sanguinamide B and its structurally related conformers Erinprit K. Singh, Deborah M. Ramsey, and Shelli R. McAlpine* In press Org. Lett. 2012 (accepted January 2012) DOI: 10.1021/ol203290n

34. 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 (accepted October 2011)

33. Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins Veronica C Ardi, Leslie D. Alexander, Victoria Johnson, and Shelli R. McAlpine* ACS Chemical Biology v6, p1357, 2011

32. 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

31. 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

30. 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, Andrea Thornquist, Chung-Mao Pan, and Shelli R. McAlpine* "A third generation of Sansalvamide A derivatives: Design and synthesis of Hsp90 inhibitors", Bio. Org. Med. Chem. Lett., v18, p6822-6856 2010

29. Erinprit K. Singh, Lidia A. Nazarova, Stephanie A. Lapera, Leslie D. Alexander and Shelli R. McAlpine* "Histone deactylace inhibitors: Synthesis of cyclic tetrapeptides & their triazole analogs" Tetrahedron Letters, v51, p4357-436, 2010

28. Victoria A. Johnson, Erinprit K. Singh, Lidia A. Nazarova, Leslie D. Alexander and Shelli R. McAlpine* "Macrocyclic Inhibitors of Hsp90", Current Topics in Med. Chem., v23, p1380-1402 2010

27. Robert C. Vasko, Rodrigo A. Rodriguez, Christian Cunningham, Veronica C. Ardi, David A. Agard, and Shelli R. McAlpine* "Mechanistic studies of Sansalvamide A-amide: An allosteric modulator of Hsp90", ACS Medicinal Chemistry Letters, v1, p4-8, 2010 DOI:10.1021/ml900003t

26. Leslie D. Alexander, Robert P. Sellers, Melinda R. Davis, Veronica C. Ardi, Victoria A. Johnson, Robert, C. Vasko, and Shelli R. McAlpine* "Evaluation of Di-sansalvamide A derivatives: Synthesis, SAR, and Mechanism of Action", J. Med. Chem. (Letter), v41, p7927-7930, 2009

25. Po-Shen Pan, Robert Vasko, Stephanie Lapera, Victoria A. Johnson, Robert P. Sellers, Chun-Chieh Lin, Chung-Mao Pan, Melinda R. Davis, Veronica C. Ardi, and Shelli R. McAlpine* "A comprehensive study of Sansalvamide A derivatives: the structure-activity relationships of 78 derivatives in two pancreatic cancer cell lines" Bio. Org. Med. Chem. v17, p5806-5825, 2009

24. Rodrigo Rodriguez, Chung-Mao Pan, William Disman, Po-Shen Pan, Robert Vasko, and Shelli R. McAlpine* "Structure-activity of Sansalvamide A derivatives and their mechanism of action in pancreatic cancer cell line PL45", J. Mex. Chem., v52, p201-211, 2008

23. Erinprit K. Singh, Robert P. Sellers, Leslie D. Alexander and Shelli R. McAlpine* "Conformational based design of macrocycles as antitumor agents" Current Opinion in Drug Discovery v11, p544-552, 2008

22. Erinprit K. Singh, Suchitra Ravula, Chung-Mao Pan, Po-Shen Pan, Robert C. Vasko, Stephanie Lapera, Sujith, Mary Kay Pflum and Shelli R. McAlpine* "Synthesis and biological evaluation of Histone Deactylase inhibitors that are based on the FR235222 scaffold", Bio. Org. Med. Chem. Lett, v18, p2549-2554, 2008

21. Melinda R. Davis, Thomas J. Styers, Rodrigo A. Rodriguez, Po-Shen Pan, Robert C. Vasko, and Shelli R. McAlpine* "Synthesis and cytotoxicity of a new class of potent decapeptides macrocycles" Org. Lett. v10, p177-180, 2008 (accepted 2007)

20. Katerina Otrubova, Gerald H. Lushington, David Vander Velde, Kathleen L. McGuire, and Shelli R. McAlpine* "A comprehensive study of Sansalvamide A derivatives and their structure-activity relationships against drug-resistant colon cancer cell lines" J. Med Chem, v51, p530-544, 2008 (accepted 2007)

19. Po-Shen Pan, Kathleen L. McGuire, and Shelli R. McAlpine* "Identification of compounds potent against pancreatic cancer cell lines" Bio. Org. Med. Chem. Lett. v17, p5072, 2007

18. Katerina Otrubova, Kathleen L. McGuire and Shelli R. McAlpine* "A scaffold targeting drug-resistant colon cancers", J. Med Chem, v50, p1999-2002 2007

17. Rodrigo Rodriguez, Po-Shen Pan, Chung-Mao Pan, Suchitra Ravula, Stephanie Lapera, Erin Singh, Thomas J. Styers, Joseph D. Brown, Julia Cajica, Emily Parry, Katerina Otrubova, and Shelli R. McAlpine* "Synthesis of second generation Sansalvamide A derivatives: Novel Templates as Potent Anti-tumor Agents" J. Org. Chem. v72, p1980-2002, 2007