Discovery & Green Chemical Synthesis of Anti-Cancer Drugs

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It costs well in excess of a billion dollars and takes over a decade to discover and develop a new drug, and once a drug is approved, manufacturing it is not cheap either. The most efficient processes generate anywhere between 25 to 100 kg of waste for every kg of product. The rising cost of drug discovery and manufacturing has ominous portents for Canada’s publicly-funded healthcare system, especially cancer care. Cancer afflicts nearly 40% of Canadians and costs the nation as much as $22.5 billion each year, and unless new technologies that accelerate discovery and eliminate inefficiencies in the manufacturing train are developed, the economic burden of much-needed anti-cancer therapeutics could soon become insupportable for our nation. Fortunately, three recent developments in the life sciences and biochemical engineering offer a way out of the current crisis. At the outset, a sizable number of the over 100,000-strong family of terpenoid natural products have been characterised as being anti-cancerous and the biosynthetic reactions involved in their assembly are now known. Secondly, the cost of oligonucleotide synthesis is declining with each passing day, and, thirdly, we can genetically engineer microorganisms such as E. coli to undertake any enzymatic reaction with unprecedented ease and precision. Consequently, we propose re-engineering the metabolism of the simple bacterium E. coli to elicit the expression of combinations, permutations and mutations of known terpenoid biosynthetic reactions to synthesize novel anti-cancer therapeutics. Specifically, we propose (1) generating a library of terpenoids for screening drug leads, (2) developing a more efficient and economical microbial-aided route for manufacturing the blockbuster anti-cancer drug paclitaxel, (3) rationally designing and synthesising of novel tubulin-binding anti-cancer drugs, and (4) synthesising a chemical library using a novel, chemical genomic approach. Not only does the research proposed herein promise to re-populate the drying pipeline of anti-cancer drug candidates with molecules that have a high likelihood of clinical approval, but microbial-aided synthesis of pharmaceuticals is the ultimate demonstration of green and continuous chemical manufacturing. Students that will be trained in the research program proposed herein will lead the next generation of drug discovery and green chemistry in industry, academia and government.