Therapeutics
Continued from page 69
8 Roder, C and Thomson, M (2015). Auranofin: Repurposing an Old Drug for a Golden New Age. Drugs R D, 15:13-20. 9 Said, M and Elshihawy, H (2014). Synthesis, anticancer activity and structure-activity relationship of some anticancer agents based on cyclopenta (b) thiophene scaffold. Pak J Pharm Sci, 27:885-92. 10Welsh, S and Corrie, P (2015). Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol, 7:122-136. 11 American Society of Clinical Oncology (2017). Olaparib Slows Growth of BRCA-Related Metastatic Breast Cancer. Online link:
https://www.asco.org/about- asco/press-center/news- releases/olaparib-slows- growth-brca-related- metastatic-breast-cancer.
basis of a multitude of successful anti-cancer treat- ments. It is no wonder, therefore, that they contin- ue to be a focus within the drug discovery industry, with drug developers understanding that their vast repertoire of molecular interactions make them fantastic anti-cancer drug candidates.
Putting heterocycles at the heart of anti-cancer drug discovery Despite the wide range of heterocyclic anti-cancer drugs currently available on the market, challenges around multi-drug resistance, poor therapeutic efficacy, adverse side-effects and poor bioavailabil- ity necessitate the continued development of novel anti-cancer agents. The majority of the drugs avail- able on the market start their drug discovery and development journey as ‘hit’ compounds in a high throughput screening assay. Take olaparib, for example, a heterocyclic
PARP-1 inhibitor that was approved by the FDA in late 2014 for the treatment of ovarian cancer (Figure 3). PARP-1 is the most abundant member of a family of poly ADP ribose polymerase (PARP) enzymes that are implicated in a range of impor- tant cellular functions including DNA repair, cell replication and differentiation and necrosis. Several forms of cancer are more dependent on PARP compared to regular cells, including those inclusive of the BRCA mutation, which rely on PARP as a critical DNA repair mechanism. This makes PARP enzymes a particularly attractive drug target in cancer research. Many PARP inhibitors mimic the nicotinamide structure of the biological molecule nicotinamide adenine dinucleotide (NAD+), which is involved in the normal function of PARP-1, in order to inter- fere with the binding of the substrate to the enzyme’s active site. Olaparib operates in this way, and by preventing cancer cells from undertaking PARP-mediated DNA repair, it is able to stop them from dividing as the cell fails to repair fatal DNA damage. A recent Phase III clinical trial of approx- imately 300 women with BRCA-related metastatic
breast cancer showed that receiving olaparib reduced the chance of progression of advanced cancer by 42%, with progression itself delayed by approximately three months11.
The development of olaparib itself started life from an initial screen of the Maybridge Compound Collection, a library of more than 53,000 hit-like and lead-like compounds. From this screen, the nicotinamide mimic S 15065 was identified as hav- ing potential activity against PARP-1. Through sys- tematic structure-activity studies based on chain elongation and substitution of the phenyl ring, the structure of S 15065 was systematically modified and improved in order to maximise the binding ability between the compound and PARP-1. This development process was made significantly easier and faster through the identification of a strong candidate ‘hit’ with desirable binding properties.
Conclusion
Due to their prevalence in nature as well as their structural and chemical diversity, heterocycles play an immensely important role in anti-cancer drug discovery. Their inclusion in approximately two- thirds of the anticancer drugs approved by the FDA in the first half of this decade highlights their ongoing importance in cancer research, with research demonstrating time and again the central role they have to play in the fight against cancer. The use of compound screening collections with a strong focus on heterocyclic-based structures can not only lead to the identification of a wide number of potentially successful drug candidates, but can also fast-track the drug development process, ulti- mately saving time, money and resources. DDW
Simon Pearce is the market segment manager for organic chemicals at Thermo Fisher
Scientific,
overseeing both the organic product portfolios of Acros Organics and Alfa Aesar. Simon joined Thermo Fisher as a synthetic chemist in 1984 as part of Maybridge, and has more than 30 years of experience in the chemical industry.
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