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Molecular modelling of novel anti-cancer molecules targeting Mortalin-p53 interaction


Project Description

Mortalin is a highly conserved member of the heat shock 70 family which, when over-expressed, plays a pivotal role in dysregulating signal pathways implicated in carcinogenesis. High mortalin levels are detected in several human malignancies including colon [1], liver, thyroid, ovarian, lung and breast carcinomas, brain tumours, melanomas [2] and various types of high grade sarcoma [Figure 1]. Its oncogenic function correlates with a critical role in directly blocking p53 tumour suppressor protein [3,4]. Over-expressed mortalin binds p53, sequesters it in the cytoplasm, and physically prevents p53 translocation into the nucleus resulting in an effective loss of p53 transcriptional function. This causes proliferative signalling and mortalin-induced expression of malignant characteristics including invasiveness and metastatic behaviour [5]. p53-dependent suppression of centrosome duplication is suppressed resulting in aneuploidy, a common feature of cancer cells. Additionally, mortalin is also known to modulate cancer cell resistance to radiation treatment and commonly used chemotherapy drugs [6].

Mortalin presents a specifically druggable target. Disrupting mortalin-p53 binding in cancer cells re-establishes p53-induced tumour-suppressive signalling [3,4,5]. Reactivated p53 provokes growth arrest and apoptosis accompanied by expression of E2F, p21CIP, p27KIP and bcl-2 family proteins; and depleting mortalin activity reverses chemotherapy drug resistance in vitro and in vivo [6]. These facts emphasise the potential of p53 reactivation as a therapeutic strategy and validate mortalin-p53 complexes as a specific anti-cancer treatment target.

Mortalin consists of a nucleotide-binding domain and a substrate-binding domain, both of which interact with different regions on the p53 molecule [7,8]. In this project we will computationally design modified cyclic peptides expected to function as highly specific nucleotide-competitive or allosteric inhibitors of mortalin-p53 docking; and aim to assay their potential as anti-mortalin/ p53 reactivator drugs. The broad profile of different types of cancer over-expressing mortalin potentially presents a wide therapeutic context for novel anti-mortalin-p53 drugs.

Research aims/ questions

1. Computational modelling of small to medium sized modified cyclic peptide molecules interfering with loop domain binding between mortalin and p53
2. Synthesis of candidate compounds using chemical and chemoenzymatic synthesis [9]
3. Validating compound activity using cell-free assay and assessing p53 reactivation
4. Using cell-based assays evaluate the potential of newly-designed molecules to function as anti-cancer drugs
5. Onward experiments will test for drugs with favourable pharmacokinetics and low toxicity to further develop the drug potential

Research training
The supervisory team are internationally recognised in the areas of histopathology, genome stability, and natural product design. This project will use a combination of advanced drug modelling and pharmaceutical discovery, cell-based assay and tumour pathology assessment methods to investigate and identify cellular components as the basis for new therapeutic strategies. Training will encompass experimental design, computational modelling, and cell and molecular biology methods. The student will benefit from integrating into the diverse and exciting environment of the University of Aberdeen.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php


Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

References

1. Dundas SR, Lawrie LC, Rooney PH, Murray GI (2005). Mortalin is over-expressed by colorectal adenocarcinomas and correlates with poor survival. J Pathol. 205 (1):74-81.

2. Nomikos A, Dundas SR, Murray GI (2012). Mortalin expression in Normal and Neoplastic Tissues. In Mortalin Biology: Stress, Life and Death, Editors Kaul and Wadhwa.

3. Wadhwa R, Takano S, Kaur K, Deocaris CC, Pereira-Smith OM, Reddel RR, Kaul SC (2006). Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. Int. J. Cancer: 118, 2973–2980.

4. Ryu J, Kaul Z, Yoon AR, Liu Y, Yaguchi T, Na Y, Ahn HM, Gao R, Choi IK, Yun CO, Kaul SC, Wadhwa R (2014). Identification and functional characterisation of nuclear mortalin in human carcinogenesis. J Biol Chem. 289(36):24832-44.

5. Na Y, Kaul SC, Ryu J, Lee JS, Ahn HM, Kaul Z, Kalra RS, Li L, Widodo N, Yun CO, Wadhwa R. (2016). Stress chaperone mortalin contributes to epithelial-mesenchymal transition and cancer metastasis. Cancer Res. 76 (9):2754-2765.

6. Yang L, Li H, Jiang Y, Zuo J, Liu W. (2013). Inhibition of mortalin expression reverses cisplatin resistance and attenuates growth of ovarian cancer cells. Cancer Lett.336(1):213-21.

7. Amick J, Schlanger SE, Wachnowsky C, Moseng MA, Emerson CC, Dare M, Luo WI, Ithychanda SS, Nix JC, Cowan JA, Page RC, Misra S (2014) Crystal structure of the nucleotide-binding domain of mortalin, the mitochondrial Hsp70 chaperone. Protein Sci. 23(6):833-42.

8. Londono C, Osorio C, Gama V, Alzate O (2012). Mortalin, Apoptosis, and Neurodegeneration. Biomolecules 2(1), 143-164.

9. Houssen WE, Bent AF, McEwan AR , Pieiller N, Tabudravu J, Koehnke J, Mann G, Adaba RI, Thomas L, Hawas UW, Liu H, Schwarz-Linek U, Smith MCM, Naismith JH, Jaspars M. (2014) An Efficient Method for the In Vitro Production of Azoline-Based Cyclic Peptides.” Angew. Chem. Int. 53 14171.

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