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Dual Mechanism of Action Anticancer Agents (GANESANAU20SF)


Project Description

The modulation of immune checkpoints and epigenetic regulation are two new strategies for cancer chemotherapy that have resulted in a number of recently approved drugs. Nevertheless, the application of immunotherapy is hampered by immune evasion arising from stem cell-like resistant tumour cells. Meanwhile, epigenetic drugs also suffer from resistance and their use is limited to relatively rare haemotological cancers.

The goal of this project is to design novel agents that combine an imminotherapeutic and epigenetic mechanism of action within a single molecule. We will merge the pharmacophores for three immunotherapy targets- indoleamine 2,3-dioxygenase (IDO), AXL tyrosine kinase and ezrin with that of three epigenetic targets- histone deacetylase (HDAC) 6, lysine-specific demethylase 1 (LSD1) and the lysine methyltransferase NSD1. A virtual library of compounds will be docked against these enzymes followed by synthesis of the predicted high affinity inhibitors. The prepared compounds will be tested in biochemical assays for enzyme inhibition and in cell-based assays for target engagement and evidence of dual mechanism of action. The initial leads will be optimised through iterative cycles to provide compounds with submicromolar target affinity and high cell permeability.

For more information on the supervisor for this project, please go here: https://www.uea.ac.uk/pharmacy/people/profile/a-ganesan

This is a PhD programme.

The start date of the project is 1 October 2020.

The mode of study is full-time. The studentship length is 3 years with a 1-year registration period.

Please note: Applications are processed as soon as they are received and the project may be filled before the closing date, so early application is encouraged.

Entry requirements:

Acceptable first degree in Chemistry, Pharmacy or Pharmacology.

The standard minimum entry requirement is 2:1.

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at View Website.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. Applicants should contact the primary supervisor for further information about the fee associated with the project.

References

i) Ruzic, D.; Petkovic, M.; Agbaba, D.; Ganesan, A.; Nikolic, K. Combined Ligand and Fragment‐based Drug Design of Selective Histone Deacetylase–6 Inhibitors. Mol. Informatics 2019, 38, 1800083

ii) Da Mota, S. R.; Bailey, S.; Strivens, R. A.; Hayden, A. L.; Douglas, L. R.; Duriez, P. J.; Borrello, M. T.; Benelkebir, H.; Ganesan, A.; Packham, G.; Crabb, S. J. LSD1 Inhibition Attenuates Androgen Receptor V7 Splice Variant Activation in Castration Resistant Prostate Cancer Models. Cancer Cell Int. 2018, 18, 71

iii) Lecointre, B.; Narozny, R.; Borrello, M. T.; Senger, J.; Chakrabarti, A.; Jung, M.; Marek, M.; Romier, C.; Melesina, J.; Sippl, W.; Bischoff, L.; Ganesan, A. Isoform-selective HDAC1/6/8 Inhibitors with an Imidazo-ketopiperazine Cap Containing Stereochemical Diversity. Phil. Trans. R. Soc. B 2018, 373, 20170364

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