Chemistry and Biochemistry
McAlpine Group
Current Projects
Our research takes a medicinal chemistry approach to the synthesis of natural products and their derivatives. We synthesize macrocyclic peptides and peptidomimetics designed to target oncogenic proteins. Working with our collaborator, Prof Steven Howell, a well established oncologist at UCSD Moores Cancer Center, our long term goal is to develop an anticancer therapeutic to treat pancreatic and colon cancers. Over the course of nine years, our lab has published on six projects involving the synthesis and biological activity of macrocycles. These projects have focused on synthesizing macrocycles that are designed from natural products or known inhibitors. By substituting new amino acids in specific positions in the macrocycle, or replacing these amino acids with triazoles, oxazoles, or thiazoles, we anticipate enhancement of their therapeutic potency. My group tests our compounds on the multiple colon and pancreatic cancer cell lines, and if they show activity, we design assays that will determine their mechanism of action.
Currently we have 4 projects being explored in the laboratory. The most advanced of these is on the synthesis and development of Sansalvamide A as an anti-cancer therapeutic. In this project, we have made over 100 analogs of the natural product Sansalvamide A, produced 3 peptidomimetics, and moved one candidate into mouse models. Currently, with the guidance of our collaborator, Prof. Stephen Howell, my graduate student is working on the formulation, solubility, and stabilization of this candidate. My student will then determine the maximum tolerated dose, and the therapeutically effective dose. Through pull-down assays, our lab has determined that this class of compounds has a unique binding site on the heat shock protein 90 (Hsp90) (using pull-down assays). Whereas most molecules bind to the N-terminus of the molecule, our compound binds between the N-M domain of Hsp90 (see attached JACS preprint that is under revision in this packet). Further, our compound demonstrates an unusual mode of action, where despite binding to the N-M domain, it inhibits C-terminal client proteins from binding to Hsp90. These client proteins are actively involved in apoptotic pathways. Thus, it appears the mechanism by which our molecules cause apoptosis, at least in part, involves inhibiting these client proteins from binding to Hsp90’s C-terminus. Additional mechanistic pathways are being investigated in our lab, including the inhibition of other Hsp90 oncogenic client proteins such as Hif-1, Vegf, and Her2 as well as examination of San’A s effect on co-chaperones including Hsp70, HIP, and HOP. Further, the synthesis of peptidomimetics where selected amide bonds are replaced with triazoles (via click chemistry) are completed and being tested for activity. The synthesis for compounds where oxazoles and thiazoles (via the Hantsch and the DAST dehydration) replace amino acids has been initiated.
Below are some examples of peptidomimetic derivatives we are currently synthesizing for our San A project:
Our second project grew out of the Sansalvamide A project, and is based on a series of decapeptides (see attached Org Lett. preprint). These decapeptides are extremely potent against pancreatic and drug-resistant colon cancer cell lines (low nanomolar cytotoxicity- see Org. Lett 2008). We have synthesized compounds for pull-down assays and determined that this class of compounds also appears to pull down Hsp90. In addition, we found that it pulls down Hsp70. Given that Hsp70 and Hsp90 form a complex in the mechanism, it is possible that this class of molecules is cytotoxic via inhibition of the complex rather than via inhibition of Hsp90 and its client proteins. Our lab is currently testing this hypothesis by running western blots and determining which of the co-chaperones, and/or client proteins are inhibited by our molecules. This exciting new series of compounds is the first in its class, and has extraordinary potential as a potent anti-cancer agent as it exhibits 5-15 nM potency against all cancer cell lines tested to date, with a ~30 fold differential selectivity between normal cell lines versus cancer cell lines, indicating it is not uniformly toxic.
Our third project involves the synthesis of macrocycles that inhibits histone deactylases (HDACs). HDACs are a promising new target for shutting down cell growth of certain cancers. Since starting this new project we have published 6 novel compounds, where 2 compounds inhibited deacetylase activity. In addition, we have completed the synthesis of peptidomimetics using click chemistry, where we are currently comparing the activity of the cyclic peptide to that of the peptidomimetic derivative.
Our recently initiated fourth project involves synthesis and mechanism of action studies on Urkelthaplestatin A (Ustat A) derivatives. Ustat A is a natural product discovered in 2008, that has known potent antitumor activity (low nanomolar). We are completing the synthesis of 6 analogs and anticipate synthesizing compounds for pull-down assays to determine their mechanism of action.