Design, synthesis and evaluation of protease-activated anti-cancer prodrugs

Matrix metalloproteinases (MMPs) are a family of endoproteases that are overexpressed in tumours and play crucial roles in many tumourigenic processes, not least tumour invasion and angiogenesis. The concept behind our technology is that the increased expression and activity of MMPs within the tumour microenvironment, relative to normal tissues, can be exploited to selectively release potent chemotherapeutics from non-toxic peptide conjugates. The result is high levels of the active agent in the tumour and negligible drug levels in ’normal’ tissues.

Conjugation of a peptide to the active drug molecule renders it inactive until such time that it is activated by MMPs in the tumour. The MMP then cleaves the peptide, resulting in release of the active drug selectively in the tumour microenvironment. The ICT has already successfully used this technology to improve the therapeutic index of a colchicine derivative (ICT2588, see Cancer Research, 2010, 70, 6902-6912), which is now licensed to University of Bradford spin-out company Incanthera Ltd (www.incanthera.com) and received global press coverage at the British Science Festival 2011 (e.g. http://www.bbc.co.uk/news/science-environment-14855666). ICT2588 is about to enter Phase I clinical trials. The group additionally has strong links with Stanford University (USA), having commercialised an MMP-activated ‘theranostic’ version of ICT2588, which simultaneously allows MRI imaging and cancer therapy (see Small, 2014, 10, 566-575, and Molecular Cancer Therapeutics, 2017, 16, 1909-1921).

The student will join a successful, motivated multidisciplinary team with expertise in medicinal chemistry, pharmacology, drug metabolism and pharmacokinetics. The project will involve the design, synthesis and biological evaluation of the next generation of MMP-activated prodrugs, with the aim of identifying an agent to progress towards advanced preclinical testing and ultimately the clinic.

Specific aims:
(1) Synthesis of novel peptide-drug conjugates, utilizing modern automated solid-phase peptide technology and/or
(2) Study of the metabolism of synthesized conjugates in tumour and normal tissues in vitro, using LC-MS;
(3) In vivo assessment of the most promising compound – pharmacokinetics and efficacy in a mouse model.