The main function of DNA is to encode the building blocks of proteins, and molecular biologists have become quite adept at cutting and pasting stretches of DNA to make nearly any protein they can envision. Unfortunately, small molecules, which are some of the most effective drugs, cannot usually be built so readily. Rather, synthetic organic chemists must use a bag of tricks and years of experience to synthesize compounds that on paper sometimes appear rather simple. However, several companies are taking advantage of a modular approach, programmed using DNA, for building diverse libraries of polyketides, naturally occurring small molecules with huge pharmaceutical promise. Two such companies include Biotica and Kosan Biosciences, which made Biotech Mashup’s list of the 15 companies with the potential to change medicine.

Polyketides, which are produced by diverse microorganisms found in places ranging from the soil to the oceans, are a structurally diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Numerous drugs spanning many therapeutic areas, such as antibiotics (e.g.erythromycin A), anti-cancer compounds and antifungals, have been derived from approximately 10,000 known polyketides. According to Biotica, polyketide natural products account for medicinal sales in excess of $20 billion per year.

The combinatorial potential of polyketide synthesis is what attracts the attention of scientists and pharmaceutical companies. Polyketide synthesis is performed by large modular multisubunit enzymes known as polyketide synthases (PKSs). The addition of each individual building block to a growing polyketide chain can be performed by a separate module of the PKS. These PKS mega-enzymes are composed of gene modules encoding the active sites for the successive activation, modification and elongation of carbon building blocks. By mixing and matching catalytic components, it is thus possible to genetically specify polyketide compounds using DNA and molecular biology. As described by Biotica, PKSs can be viewed as molecular assembly lines, in which every element of functionality of the polyketide product can be identified with a specific enzyme workstation.  It is estimated that a polyketide synthesis system with just 6 modules can theoretically produce over 100,000 compounds. Large polyketide libraries can be generated by assembling a gene with various combinations of altered DNA fragments. Novel compounds can also be produced using synthesized “starter units” that are fed to engineered microorganisms to be used as precursors.

Kosan is currently focusing on anti-cancer compounds, and has numerous drugs in its pipeline spanning the preclinical to Phase 2 development phases. Compounds currently in Phase 2 development target breast cancer, melanoma, and multiple myeloma. Biotica also has a portfolio of anti-cancer compounds, and is partnering with Wyeth on its mTOR inhibitor anti-cancer drugs. Importantly, both Biotica and Kosan are targeting Hsp90 (heat shock protein 90), a protein that interacts with several sets of signaling proteins and whose disruption leads to degradation of the interacting proteins that can promote cancer.

The ability to “program” small molecule synthesis in a combinatorial fashion is truly exciting. Given the proven utility of polyketides as drugs, we have good reason to believe there will be some great drugs coming from Biotica and Kosan.