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Final Report Summary - NHELMIMACANL (Novel Alpha-Helix Mimetics as Anti-Cancer Leads)


Breast cancer is the major cancer affecting women. According to the report “Breast Cancer -an Environmental Disease: The Case for Primary Prevention”, in the UK alone the disease claims around 11,800 lives every year. Female breast cancer incidence is strongly related to age, with the highest incidence rates overall being in older women, supporting a link with hormonal status. Tamoxifen is an Estrogen Receptor (ER) antagonist that has been used for the systematic treatment of patients with breast cancer for nearly three decades. While about half of patients immediately fail to respond to Tamoxifen, even in the responding patients the disease ultimately progresses to a resistant phenotype. Aromatase inhibitors, which disrupt the body’s endogenous synthesis of Estrogen, are often co-prescribed to slow this resistance onset. There remains however much scope for the development of additional drugs for breast cancer treatment that can be prescribed either for patients not responding to tamoxifen, for patients having developed resistance to it, or as cotherapeutics to slow resistance onset. Liver Receptor Homologue 1 (LRH-1) is a nuclear receptor (NR) that is implicated in the regulation of ER expression. A small molecule able to selectively inhibit LRH-1 therefore has great potential as a co-therapy for the more effective treatment of breast cancer.

Protein Protein Inteactions (PPIs) are ‘in-the-spotlight’ currently as targets for drug development. They play a key role in a number of cellular processes, including the growth of tumours. Small molecule PPI inhibitors are attractive as new therapeutic leads and as probes for the understanding of cellular signaling pathways.

The research conducted in this Marie Curie IEF Project was led by Dr. Olga Bodero (fellow) and Prof. Alan C. Spivey (principal investigator) and was aimed at the development of a new series of small, drug-like molecules designed to mimic five amino acid side-chains presented by α-helical secondary structure elements that constitute binding ‘hot-spots’ on protein surfaces. The transcription activities of NRs such as LRH-1 and other NRs such as the Androgen Receptor (AR), which is integral to prostate cancer, are regulated in vivo by PPIs involving such alpha-helical motifs and so the mimetics targeted in this research have been designed to selectively regulate these interactions and so constitute potential anti-cancer therapeutic leads.

Using computational tools and the available X-ray structure of the proteins of interest, a small bicyclic molecule was selected as a pivotal scaffold from which to present the amino acid side chains in the correct spatial orientation to mimic an alpha-helical protein surface. Starting from cheap, commercially available starting materials the precursors of the bicyclic core were synthesized on a large scale. Then, by a thermal reaction the bicyclic core already bearing two of the five required amino acid residues was obtained in good yield. The fellow was able to successfully introduce the third and forth residues by carefully manipulating the functional groups in the molecule. The key steps of the synthetic route were carefully optimized then scaled-up. Molecules containing mimics of residues designed to target both LRH-1 and the AR were prepared. the two series of compounds were prepared by synthetic sequences that followed similar synthetic approaches with slightly different starting materials. Unfortunately, although these advanced intermediates of the proposed target molecules were synthesized and fully characterized for both the ER and the AR series, unexpected reactivity in the last steps of both series made it impossible to deliver final samples for biological testing. As a consequence, a new synthetic route was designed and this approach is currently being progressed to an advanced stage in the Spivey Group.

The Project was designed to cause a major impact in the European excellence due to its multidisciplinarity. As an example of this, it is noteworthy to mention the use of modern computational techniques in the design of new drugs. This is currently a trend in the pharmaceutical industry and therefore there is a clear need of professionals trained in those techniques. The research described herein has allowed the Fellow to develop these key skills and should allow future insights from academic research to be developed into new therapeutic advances in the future.

During the course of the research project Olga became expert in the use of Gaussian, Glide and a number of other computational software packages related to molecular modelling (DFT), docking and molecular dynamics. As well as attending many Scientific Meetings during her Fellowship, she also attended a Workshop in Munich on European Patent Law relating to Pharmaceutical regulation.

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