Preclinical investigation of novel super-selective mTOR inhibitors in colorectal cancer

Dr Asier Unciti-Broceta, Professor Owen Sansom, Professor Margaret Frame

The development of potent and selective small molecules that mediate dose-dependent inhibition of a protein in its natural environment is essential to elucidate the role of such nominated target in normal and pathological settings [1]. This is especially true in cancers where multiple aetiological factors are involved in tumourigenesis and cancer progression. The mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that operates as the catalytic subunit of two multiprotein complexes, mTORC1 and mTORC2. These complexes act as sensors that integrate multiple extracellular and intracellular signals to coordinate cell metabolism, proliferation, survival and migration. Increased mTOR kinase activity is found in approximately half of all human malignancies including colorectal cancer, via genetic dysregulation of different upstream regulators of mTORC1 and / or mTORC2 signalling. Rapalogs (rapamycin, everolimus) are a family of clinically approved macrolide drugs that stops mTORC1 signalling through an allosteric interaction that does not occur in the mTORC2 complex, thus inhibiting mTORC1 activity with superb selectivity [2]. Sansom’s lab demonstrated that mTORC1 is an essential downstream effector of Wnt-signalling in the intestine and showed that treatment of APC-deficient colorectal adenomas with rapalogs causes tumour cells to undergo growth arrest and differentiation [3]. However, following further mutation in KRAS, rapalogs are no longer sufficient to control tumour growth [4], highlighting the need for broader inhibition of mTOR. Furthermore, other studies have also shown that mTORC2 is an important driver of cancer cell proliferation and survival in other malignancies [5]. By the simultaneous inhibition of both complexes, small molecules that block the kinase domain of mTOR are optimal to challenge rapalogs and establish whether one or both complexes need to be blocked to achieve maximal anticancer effect in different cancer types and subtypes. The problem is that current mTOR inhibitors also inhibit other related kinases (e.g. PI3K), making impossible to dissect the differential effects of blocking one or both complexes in a pharmacological manner. Finally yet importantly, although mTOR inhibitors display superior anticancer activities than rapalogs against most cancers [5], their off-target activity results in dose-limiting toxicities that have so far precluded their regulatory approval.

Unciti-Broceta and Frame (Edinburgh) have discovered a novel class of super-potent mTOR inhibitors with unprecedented selectivity for its target when compared with the rest of the kinome (see Figure) and high antiproliferative potency against cancer cells, but not normal cells [Unpublished results, patent in preparation]. In collaboration with Sansom (Glasgow), we propose to use these best-in-class dual mTORC1/2 inhibitors and mTORC1-selective rapalogs to elucidate the role of mTOR Complex 1 and 2 in genetically engineered mouse models (GEMMs) of colorectal cancer (CRC) in cell culture, tumour organoids and in vivo. Results from the screens will inform the medicinal chemistry lead optimisation campaign and / or nominate a clinical candidate. By using a wealth of medchem methods, cell assays, imaging and molecular biology techniques, and animal models, this truly multidisciplinary project will provide the student with a unique set of skills and ―at the same time― will accelerate the preclinical development and translation of a promising class of inhibitors with high therapeutic potential. 

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