We are currently working on four organic synthesis projects and three
biology projects. We are currently funded by three large grants for
several of our projects: two are from NIH and the third is from the Frasch
Foundation totaling ~ $2,057,500. We have also received support from
several other agencies including CSUPERB, the Howell foundation, and Pfizer, to
name a few. Thus, we are actively recruiting students. We are looking for
both synthetic chemists and biology students to do research in our group. The
synthesis in our group varies from making peptidomimetics using click chemistry
to utilizing the Hantsch reaction and DAST dehydrations 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 18
cancer cell lines (including colon, pancreatic, lung, 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. In addition, we have initiated
computational docking studies, thus, students may also participate in molecular
modeling.
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 are also utilizing 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.
Since
January 2006 we have published thirteen papers on three synthetic projects, and
have two more papers submitted for publication (July 2009). We have published
25 papers since my lab started at SDSU in 2001, and we currently have four
patent applications. We have presented our work extensively in the community.
I have given 47 invited seminars since starting at SDSU and my students have
presented 64 posters at meetings around the world (including presentations in
Australia, England, ShangHai, and at Gordon conferences)! I expect my students
to present at least once at a national or international meeting and to publish
an average of three papers while in my laboratory.
Being
an associate, tenured professor, I have established a full-fledged research
program in organic synthesis, and have initiated biological assays on the
compounds we synthesize. Via my developed research program we plan to maintain
publishing with the same frequency as we have accomplished in the past and I
work with my students so that they typically publish on average one paper/year
that they are in my lab. Thus, I feel the community knows our work, which
helps my students find jobs, enter graduate programs, 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. My masters’ students typically graduate
with a minimum of two papers but often three, and I expect PhD students to
graduate with a minimum of five papers (the most recent PhD to graduate has 12
publications to date). Thus, we are a relatively productive group. In
addition, we raise money (~$3,500,000 to date) to fund our research (a total of
109 fellowships) and travel to meetings. We currently have funding from or
have been funded in the last year by: NIH (2 R01 grants and an R03), Frasch
Foundation, CSUPERB, Pfizer, MIRT, and the Howell Foundation. We have close
ties to a number of local 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 including:
Ph.D. programs in organic chemistry at UCI, UCSB, UPenn, Scripps, and the
prestigious Ph.D. program at NIH-oxford university (accepts 6 student out of
~1000 applicants). In addition, my students obtain excellent Post-doctoral
opportunities with the most recent being with Prof. Gary Molander at UPenn.
Finally, students choosing to go into industry have successfully obtained jobs
after their degrees as organic chemists at local biotech companies including:
Pfizer, Johnson and Johnson, Merck, Neurocrine, Ligand, Ambit, and the Burnham
institute. 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.
PUBLICATIONS
27) Leslie D.
Alexander, Robert P. Sellers, Melinda R. Davis, Victoria A. Johnson, Veronica
C. Ardi, and Shelli R. McAlpine* A potent new class of Hsp90 inhibitors:
Di-sansalvamide A derivatives, submitted, 2009
26) Robert C. Vasko,
Rodrigo A. Rodriguez, Christian Cunningham, Veronica C. Ardi, David A. Agard, and
Shelli R. McAlpine* Mechanistc studies of Sansalvamide A-amide: A potential
allosteric modulator of Hsp90, Re-revision to J. Am. Chem. Soc. 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. in press, 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
16) Thomas J. Styers,
Ahmet Kekec, Rodrigo Rodriguez, Joseph D. Brown, Julia Cajica, Chris L.
Carroll, Po-Shen Pan, Irene Medina, Ricardo Corral, Jennifer V. C. Johnston,
Emily Parry, Stephanie Lapera, Katerina Otrubova, Kathleen L. McGuire,* and
Shelli R. McAlpine* Synthesis of Sansalvamide A derivatives and their
cytotoxicity in colon cancer cell line HT-29 Bioorganic and Medicinal
Chemistry, v14, p5625-5631 , 2006
15) Po-Shen Pan,
Fiona A. Curtis, Chris L. Carroll, Irene Medina, Lisa A. Liotta, Gary J.
Sharples, and Shelli R. McAlpine*, “Novel Antibiotics: C-2 symmetrical
macrocycles affecting Holliday Junction DNA processing” Bioorganic and
Medicinal Chemistry,v14, p4731-4739, 2006
14) Katerina
Otrubova, Thomas J. Styers, Po-Shen Pan, Rodrigo Rodriguez, Kathleen L.
McGuire,* and Shelli R. McAlpine*, “Synthesis and novel structure-activity
relationships of potent Sansalvamide A derivatives” Chemical
Communications p1033-1034, 2006
13) Thomas J.
Styers, Rodrigo Rodriguez, Po-Shen Pan, and Shelli R. McAlpine*, “Synthesis
of novel Sansalvamide A Derivatives via new, high yielding macrocyclization
conditions” Tetrahedron Letters, v47, p515-517, 2006
