WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Overview

 

The Drug Discovery Unit (DDU) integrates medicinal, computational and synthetic chemistry with advanced biochemical and biophysical assays, in vitro cellular biology and in vivo capability to develop novel and first in class therapeutics for the treatment of unmet needs in cancer patients. The Unit has established facilities to enable state-of-the-art biological and clinical target assessment and validation, small molecule drug design and synthesis and the biological evaluation of the resultant compounds, and a track record of bringing projects from target validation to the clinic. The DDU builds upon fundamental biology discoveries made within the CRUK Manchester Institute to investigate novel drug discovery targets and to provide new chemical entities for the treatment of cancer.

 

Despite the impact of the coronavirus pandemic during the past year, research and laboratory work has continued apace during 2021, in a COVID-safe manner. We have strengthened our collaboration with colleagues in the CRUK Manchester Institute, and are working closely with Prof Iain Hagan, Prof Richard Marais and Dr Claus Jorgensen to advance drug discovery efforts against exciting targets involved in cancer cell cycle, in cancer cell stemness and resistance and in tumour stroma regulation, as well as progressing our suicide gene therapy for the treatment of solid tumours. We have actively sought to integrate our projects with Caroline Dive’s biomarker discovery programme wherever possible, so that all nominated targets have selection and predictive biomarkers. We have fostered close collaborations with our clinical colleagues at the Christie NHS Foundation Trust on a number of late stage projects.

 

 

Research highlights of 2021 include new promising results with our lysyl oxidase (LOX) inhibitors in models of pulmonary fibrosis and metastasis, and the discovery and biological assessment of very potent, selective and bioavailable inhibitors of several collaborative cancer targets which are advancing towards or through lead optimisation.

 

In 2021 two of our late stage projects, the RAF+SRC inhibitor 3833 and the LOX inhibitors, were selected from nearly 90 submissions by the Alderley Park Oncology Development Programme, a national programme designed to develop and progress start-up oncology projects. The programme, funded by Innovate UK and CRUK and backed by a consortium of global pharmaceutical and healthcare companies, aims to identify exciting oncology innovations that will improve the diagnosis and treatment of cancer and to help accelerate their progression towards commercialisation. Both our RAF+SRC and LOX projects reached the final stage of the programme as part of a select group of only six projects from the whole of the UK.

 

RAS-driven cancers such as pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma (CRC) and non-small cell lung cancer (NSCLC) account for about one third of human cancers. Despite over 40 years of research, most RAS-driven cancers remain areas of unmet clinical need and patients with these cancers still generally receive conventional chemotherapy – often with limited efficacy and potentially high toxicity. Multiple signalling pathways are activated in KRAS-mutant cancers, and blocking only one target or one pathway is often ineffective or has paradoxical consequences. For example, drugs targeting mutant BRAF cause KRAS-mutant tumours to grow, because KRAS uses another RAF pathway protein, CRAF, instead of BRAF, to signal. In addition, RAS-mutant cells also require SRC, a controller protein for multiple parallel signalling pathways, to signal cells to proliferate.

 

 

The joint teams of Prof Springer and Prof Marais discovered 3833, an oral inhibitor for RAS-driven cancers with a unique mechanism of action as a bi-nodal RAF (BRAF and CRAF) + SRC inhibitor that targets these two key signalling pathways and so is effective in both BRAF-mutant and KRAS-mutant cancers (Figure 2A). A Phase I clinical trial (NCT02437227) at the Christie and Royal Marsden NHS Foundation Trusts, has shown that 3833 is well-tolerated by patients, with evidence of responses. 3833 significantly prolonged progression-free survival and partial response in a patient with a KRAS-driven spindle cell sarcoma who did not respond to the third-generation kinase inhibitor ponatinib and therefore had limited treatment options. This project was selected for the drug development programme at Alderley Park, with the aim of accelerating its progression to Phase II clinical trial and a subsequent route to approval.

 

Lysyl oxidases (LOX/LOXL1-4) crosslink collagens and elastin, stiffening the extracellular matrix (ECM). In collaboration with Prof Marais, we have discovered LOX and LOX family inhibitors with good pharmacological and pharmacokinetic properties. Our inhibitors have been designed to prevent the crosslinking of the ECM, which is a key step in the progression of pulmonary fibrosis, a disease that severely affects the quality of life of large numbers of patients. LOX also has important roles in the progression of tumour metastasis, which is the major cause of death in cancer patients. LOX inhibitors address large unmet needs as there is currently no effective therapeutic option for cancer metastasis and pulmonary fibrosis. We have already demonstrated therapeutic activity in primary tumour models of CRC, PDAC and breast cancer as well as anti-metastatic efficacy in preclinical models. New data in the bleomycin-induced model of pulmonary fibrosis have shown a marked reduction of positron-emmision tomography (PET) marker of fibrosis upon treatment with our LOX inhibitors (Figure 3). This is the second project selected by the Alderley Park Oncology Development Programme to be supported towards accelerating selection of a candidate drug to progress to toxicology and preclinical development studies before moving into early clinical trials in patients, as monotherapy and in combinations.

 

 

We have continued our collaboration with IDEAYA Bioscience and with Stephen Taylor at The University of Manchester on in vivo model assessment for our Poly(ADP-ribose) glycohydrolase (PARG) inhibitors, for the treatment of ovarian, gastric and breast cancer. IDEAYA Bioscience is planning to file an IND by Q4 2022.

 

The DDU has a healthy portfolio of advanced small molecule inhibitors and biologics projects that are in lead identification, lead optimisation or later stages (Figure 4). The exciting potential of many of our projects has raised great commercial interest and we are looking to accelerate the progress of these projects with commercial funding.