Research in our lab is primarily concerned with the total synthesis of known and novel small molecules exhibiting unique biological activity of therapeutic importance, and the use of such molecules to solve problems relevant to human disease.
Natural products often serve as inspiration for synthetic innovation due to their unique molecular structure. Frequently their bioactivity is also inspiring, for example they may exhibit remarkable potency and/or selectivity for a particular biological target, or perturb biological systems through an unexplored but therapeutically promising mode of action. In many cases the supply of a natural product is limited due to poor isolation yield coupled with structural complexity that prohibits practical synthetic access using existing methods and strategies. This could be addressed through synthetic innovation. Additionally, modern organic synthesis allows us to not only study the biological properties of the natural product itself, but to design and synthesize improved versions that could be optimized for therapeutic and other uses.
Thus the activities in our lab are divided along two main lines: (1) the development, through innovative synthetic strategies and methods, of practical synthetic routes to targets of interest that can supply quantities needed for further study and that are amenable to the rapid generation of a diverse set of analogs, and (2) the design and synthesis of optimized analogs and their subsequent use in our lab and by collaborators to study the disease of interest and to develop new therapies and tools.
These approaches are applied in our lab to therapeutic problems for which there are currently no treatments or only poorly effective treatments. Examples of such problems are tumor metastasis and triple-negative breast cancer.
Improving the Affinity of SL0101 for RSK Using Structure-Based Design. Mrozowski RM, Vemula R, Wu B, Zhang Q, Schroeder BR, Hilinski MK, Clark DE, Hecht SM, O’Doherty GA, Lannigan DA. ACS Med.Chem. Lett. 4, 175–179 (2012).
Insights into the Inhibition of the p90 Ribosomal S6 Kinase (RSK) by the Flavonol Glycoside SL0101 from the 1.5 Å Crystal Structure of the N-Terminal Doman of RSK2 with Bound Inhibitor. Utepbergenov D, Derewenda U, Olekhnovich N, Szukalska G, Banerjee B, Hilinski MK, Lannigan DA, Stukenberg PT, Derewenda ZS. Biochemistry 51:6499–6510 (2012).
Analogues of the RSK Inhibitor SL0101: Optimization of In Vitro Biological Stability. Hilinski MK, Mrozowski RM, Clark DE, Lannigan DA. Bioorg. Med. Chem. Lett. 22:3244–3247 (2012).
Function-Oriented Synthesis: Biological Evaluation of Laulimalide Analogues Derived from a Last Step Cross Metathesis Diversification Strategy. Mooberry SL, Hilinski MK, Clark EA, Wender PA. Mol. Pharmaceutics 5:829–838 (2008).
Pharmacophore Mapping in the Laulimalide Series: Total Synthesis of a Vinylogue for a Late-Stage Metathesis Diversification Strategy. Wender PA, Hilinski MK, Skaanderup PR, Soldermann NG, Mooberry SL.Org. Lett. 8:4105–4108 (2006).
Total Synthesis and Biological Evaluation of 11-Desmethyllaulimalide, a Highly Potent Simplified Laulimalide Analogue. Wender PA, Hilinski MK, Soldermann NG, Mooberry SL. Org. Lett. 8:1507–1510 (2006).