> Research & Grants
> Grants Program
> Research Grants
> Research Grants Awarded
Research Grants Awarded
The Synthesis and Molecular Pharmacology of Cephalostatin 1, a Possible p16INK4a Synthetic Lethal Compound
The natural product cephalostatin 1 is one of the most promising cytostatic compounds ever screened by the National Cancer Institute (average GI 50 =1.8nM). In addition to its potency, the COMPARE statistical analysis of cephalostatin 1’s anti-proliferate activity indicates it possesses a unique and undiscovered mechanism of action. Recently, cephalostatin 1 was determined to selectively target cancer cell lines possessing a dysfunctional p16 INK4a tumor suppressor gene. The importance of p16 INK4a as a tumor suppressor gene is indisputable, and p16 INK4a is inactivated in over 80% of breast cancer tumors. A compound that selectively targets cells exhibiting an inactivated gene could be defined as a ‘synthetic lethal’ molecule, and a p16 INK4a synthetic lethal compound would possess enormous potential as a chemotherapeutic drug capable of selectively targeting tumor cells. In addition, a p16 INK4a synthetic lethal compound would also be an immensely valuable chemical genetics reagent in studying the function of p16 INK4a in cells. Further, uncovering the mode of action of a p16 INK4a synthetic lethal compound could identify a new class of cancer specific cellular targets for the development of pharmaceutical agents. Unfortunately, the low natural abundance of cephalostatin 1 has prevented exploration of the compound’s molecular pharmacology and its potential as a lead pharmaceutical agent. Therefore, access to substantial amounts of cephalostatin 1 may only be achieved through total synthesis. This research project will 1) complete a concise, flexible, and scalable total synthesis of cephalostatin 1 2) determine the structure activity relations of cephalostatin 1 and identify simplified biologically active analogs 3) synthesize biologically active probe derivatives of cephalostatin 1 4) characterize the biological activity of cephalostatin 1 in cell culture including determining whether cephalostatin 1 is a synthetic lethal compound for p16 Ink4a 5) identify the cellular target(s) of cephalostatin 1.
Cancer is a disease of uncontrolled cellular proliferation. In order to become capable of limitless reproduction, cancer cells must inactivate critical regulators of cellular division, termed tumor suppressors. The inactivation of certain tumor suppressors is a universal feature of tumor cells. p16 INK4a , one of the most critical tumor suppressors known, is inactivated in over 80% of breast cancers. A drug capable of targeting cells with inactivated tumor suppressors would be an ideally selective treatment capable of destroying cancer cells without affecting untransformed tissue. Recently, researchers at the National Cancer Institute (NCI) screened the activity profiles of over 50,000 compounds for agents that selectively targeted cancer cells with inactivated p16 INK4a , and the natural product cephalostatin 1 was determined to be the most selective compound at inhibiting the proliferation of p16 INK4a defective cells. Originally isolated over 30 years ago from an Indian Ocean marine invertebrate, cephalostatin 1 is one of the most promising compounds ever screened by the NCI. Cephalostatin 1 was determined to inhibit the proliferation of cancer cells at very low concentrations, and an initial characterization of its biological activity indicates the compound inhibits cancer cell division through a novel and undiscovered mechanism. Unfortunately, the amount cephalostatin 1 obtained from the natural source was insufficient to fuel the exploration of the compound’s promising biological activity and the evaluation of its potential as a lead cancer pharmaceutical. This proposal outlines a proposed laboratory total synthesis of cephalostatin 1. The synthetic cephalostatin 1 produced will fuel the described experiments that will uncover the novel mechanism through which cephalostatin 1 halts the proliferation of cancer cells. It will be determined conclusively whether cephalostatin 1 selectively targets p16 INK4a defective cells, and cephalostatin 1 could be an important reagent in furthering the understanding of p16 INK4a function. Cephalostatin 1 analogs will also be synthesized and evaluated to identify simplified compounds that posses the unique anti-proliferative activity, and the initial evaluation of cephalostatin 1 as a cancer pharmaceutical will be performed.