Tumour-Specific Delivery of MCL1 Inhibitors Using Novel Peroxynitrite Cleavable Antibody-Drug Conjugates


   Department of Chemistry

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  Prof Steven Bull, Dr James Hodgkinson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

We invite applicants for a 4-year iCASE studentship to work in collaboration with our industrial partner Isogenica

Additional Supervisor: Prof Martin Dyer, University of Leicester

• The startling statistic that 1 in 2 people will develop some form of cancer during their lifetime means there is an urgent need to develop new precision cancer medicines. However, many cancer drugs adversely affect healthy cells, causing serious side effects and preventing these drugs from progressing clinically. 

• MCL1 is an important cancer drug target, suppressing programmed cell death (apoptosis) in many malignancies. However, clinical trials with specific MCL1 inhibitors have been halted due to cardiotoxicity. 

• Antibody-mediated delivery of MCL1 inhibitors specifically to malignant B-cells using antibody drug conjugates (ADCs) could harness the high therapeutic potential of MCL1 inhibitors, whilst removing toxicities. 

• This studentship will involve chemical synthesis and biological evaluation of novel ADCs for the targeted delivery of potent MCL1 inhibitors to malignant B-cells. 

• You will join a highly interdisciplinary chemical/biology project, involving the synthesis of novel MCL1 ADCs using a novel linker, cleavable only in malignant B-cells with high ROS levels.  

• You will have an industrial placement in Cambridge with Isogenica, who will provide B-cell specific VHH antibodies.

• The studentship will provide a unique portfolio of chemical and biological skills necessary for a career in life sciences in academia/biotech or drug discovery in the pharmaceutical industry. 

Enquiries

Project Enquiries to [Email Address Removed]

Programme enquiries to [Email Address Removed]

To apply please refer to

https://more.bham.ac.uk/mrc-aim/phd-opportunities/


Biological Sciences (4) Chemistry (6) Medicine (26)

Funding Notes

The competition funding provides students with:
4 years of stipend at UKRI rates
4 years of tuition fees at UK fee rates (Plus one award of a full overseas fee waiver to an international applicant)*
RTSG
Budget to help with the cost of purchasing a laptop
The University of Leicester will provide full overseas fee waivers for the duration of their study to all international students accepted at Leicester. The funder, UKRI, allows us to appoint up to 30% overseas students.

References

[1] A.H. Wei et al., Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood reviews, 2020 44, 100672.
[2] X. Wang et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes & development, 2013 27(12), 1351-1364.
[3] A. Kotschy et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature, 2016 538(7626), 477-482.
[4] Z. Fu et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal transduction and targeted therapy, 2022 7(1), 93.
[5] T.D. Nguyen et al. Mechanisms of ADC toxicity and strategies to increase ADC tolerability. Cancers, 2023. 15(3), 713.
[6] L. Wu et al. Dual-channel fluorescent probe for the simultaneous monitoring of peroxynitrite and adenosine-5′-triphosphate in cellular applications. J. Am. Chem. Soc., 2021 144, 174-183.
[7] M. L. Odynieuc et al, Peroxynitrite activated drug conjugate systems based on a coumarin scaffold toward the application of theranostics, Frontiers Chem., 2019, 775.
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