University of Pittsburgh Cancer Institute (UPCI)

Chemical Diversity

PX-866This group of CTP investigators is focused on designing new methods for the synthesis of complex, cancer-relevant small molecules, using combinatorial chemistry methods. These researchers often collaborate closely with the UPCI Chemical Biology Facility.

Selected Publications

  • Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency, and synthesis of the second generation lead kb-NB142-70, which has excellent potency and selectivity (Bravo-Altamirano et. al., ACS Med Chem Lett. 2:154-159, 2011).
  • The natural product (--)-dictyostatin is a microtubule-stabilizing agent that potently inhibits the growth of human cancer cells, including standard chemotherapy agent paclitaxel-resistant clones. Extensive structure-activity relationship studies have revealed several regions of the molecule that can be altered without loss of activity. The most potent synthetic dictyostatin analogue described to date, 6-epi-dictyostatin, has superior in vivo antitumor activity against human breast cancer xenografts compared with paclitaxel. In spite of their encouraging activities in preclinical studies, the complex chemical structure of the dictyostatins presents a major obstacle for their development into novel antineoplastic therapies. A highly convergent chemical synthesis method was used to generate new the analogs 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin, which induced mitotic arrest and microtubule assembly in vitro and in intact cells. Both compounds inhibited the growth of paclitaxel- and epothilone B-resistant cell lines at low nanomolar concentrations, synergized with paclitaxel in a human breast cancer cell line, and had antiangiogenic activity in transgenic zebrafish larvae (Vollmer LL et. al., Mol Cancer Ther 10:994-1006, 2011).
  • Red algae are a prolific source of squalene-derived polyethers that show moderate to high levels of cytotoxicity and very selective protein phosphatase 2A (PP2A) inhibition. CTP investigators have reported the first total synthesis of lactodehydrothyrsiferol, the longest linear sequence in a 16-step route. This is the shortest route that has yet been reported for any member of this molecule class (Clausen DJ et. al., Angew Chem Int Ed Engl 50:5178-81, 2011).
  • Two new chemical methodologies were developed as a source of small-molecule probes and as a drug discovery starting point. The first was a pathway-based screen for DNA damage checkpoint inhibitors, and the second was a focused library approach for inhibitors of the heat-shock protein Hsp70 (Huryn DM et. al., Proc Natl Acad Sci USA 108:6757-62, 2011).

Members

Curran, Dennis, PhD
Chemistry
Nelson, Scott, PhD
Chemistry
Deiters, Alexander PhD
Chemistry
Wilcox, Craig, PhD
Chemistry
Floreancig, Paul, PhD
Chemistry
Wipf, Peter, PhD
Chemistry
Koide, Kazunori, PhD
Chemistry
Xie, Wen, MD, PhD
Pharmaceutical Sciences
Li, Song, MD, PhD
Pharmaceutical Sciences