Discovery of ERK5 inhibitors for biomarker-driven clinical evaluation in cancer

Lead Research Organisation: Newcastle University
Department Name: Northern Institute for Cancer Research

Abstract

Cancer is now the commonest cause of death from disease in the UK, and increasingly in all developed countries. In the UK, prostate cancer is the most common malignancy in males, breast cancer the most common in females and, worldwide, liver cancer is the 3rd most common tumour type. Therapeutic options for the common cancers remain limited, and only drug therapy is of proven benefit for the management of metastatic disease, the primary cause of death in cancer patients. Although the range and activity of drugs available for cancer treatment are improving, over 150,000 patients still die of the disease in the UK each year. Hence there remains a substantial unmet clinical need, and ERK5 is an exciting new drug target in multiple tumours including prostate, breast and liver cancer.

Selective and potent inhibitors of the signalling enzyme ERK5 will be developed and a clinical trial candidate and a back-up compound identified during the 2 year MRC DPFS award. Subsequently, the compound(s) will be evaluated in patients with cancer and the clinical development pathway for new cancer medicines is well-defined. Importantly, ERK5 inhibitors are representative of the new generation of targeted cancer drugs and hence a comprehensive portfolio of tests or biomarkers is essential for the optimal pre-clinical and clinical development of drug candidates, and their eventual use as stratified medicines - i.e. making sure that the right patient gets the right drug at the right time. These biomarkers will be developed alongside the drug candidate using invasive (biopsy) and non-invasive (imaging) technologies.

The research output, a new drug in a new class, will provide an exciting new treatment option for patients with cancer. Furthermore, the co-development of biomarkers will allow the treatment to be directed towards those patients who are most likely to benefit, and allow the early evaluation of the therapeutic potential of ERK5 inhibitors.

Technical Summary

Extracellular regulated kinase 5 (ERK5, BMK1, MAPK7) is the terminal kinase in one of the 4 major mitogen activated protein (MAP) kinase pathways. MAP kinase pathways are central to cancer, as well as numerous other pathologies. Recent success with B-RAF inhibitors in melanoma, and ongoing clinical trials with MEK1/2 inhibitors, has demonstrated that these pathways are drug-able. Correlative clinical data have identified ERK5 as a target in a number of tumour types, including prostate, breast and liver cancer, and mechanistic studies have demonstrated a tumour-type dependent role for ERK5 in cell proliferation, survival, invasion, and/or angiogenesis. Importantly, recent encouraging pre-clinical data using a small molecule ERK5 inhibitor (XMD8-92) demonstrated pronounced inhibition of in vivo tumour growth.

In collaboration with the CR UK Beatson Institute (Professor Hing Leung), the Babraham Institute (Dr Simon Cook) and Cancer Research Technology, Newcastle has identified two novel series of potent and highly selective ERK5 inhibitors. The lead series has low MW and high ligand efficiency, sub-microM activity against ERK5, no activity against 131 other kinases in a screen which included 10 ERK/p38/JNK isoforms, low microM inhibitory activity in a cell-based ERK5 reporter gene assay, together with excellent solubility, in vitro metabolic stability and plasma protein binding properties. The lead compound series was identified by a high-throughput screen (HTS) of ~160,000 compounds, which has also identified a back-up series.

The current application is for support to undertake lead optimisation in the primary lead series, and hit validation and hit-to-lead studies on the back-up series, supported by structure-based drug design. In addition to identifying a clinical trial candidate, a comprehensive portfolio of invasive and non-invasive biomarkers will be developed to facilitate hypothesis-testing early phase clinical trials.

Planned Impact

The end beneficiaries will be cancer patients, the pharmaceutical industry and healthcare providers, as well as the academic community.

Cancer Patients: The ERK5 pathway has been implicated in a number of tumour types. By virtue of the anti-invasive, anti-angiogenic and anti-vascular effects of ERK5 inhibitors, potentially all solid tumour patients may benefit from treatment with an ERK5 inhibitor. There are strong data for the most common cancer types in men (prostate) and women (breast), and for liver cancer (the 3rd most common cancer worldwide). In the UK (http://info.cancerresearchuk.org) there are 37,000 new cases of prostate cancer and 10,400 deaths, and 48,000 new cases of breast cancer and 11,600 deaths, annually. For liver cancer there are 748,000 new cases and 696,000 deaths globally each year. ERK5 over-expression is observed in 20-25% of prostate, breast and liver cancer samples, and hence sizeable numbers of cancer patients have the potential to benefit from an ERK5 inhibitor.

The Pharmaceutical Industry: ERK5 is a novel target identified by academic groups, including two of the Co-Investigators (Leung ,Cook). Industry has recognised the need to source novel cancer targets and therapeutics from academia and the proposed in vivo proof-of-concept studies, and the discovery of ERK5 inhibitors and associated biomarkers suitable for clinical use, will meet this need for ERK5. Globally, annual sales for the majority of targeted anticancer drugs approach or exceed 1 Billion US dollars.

Healthcare Providers: Due to the high incidence of the disease and the inadequacy of current treatments, cancer places major demands on healthcare resources and effective new therapies are urgently needed. The proposed development of both a drug (an ERK5 inhibitor) and associated biomarkers for patient stratification, will ensure that costs for healthcare providers are minimised by restricting the use of an ERK5 inhibitor to only those patients who are most likely to benefit.

The ultimate potential impact of the research will be increased therapeutic options for cancer patients, reduced morbidity and mortality from cancer, and increased pharmaceutical and biotechnology company, and thereby national, wealth due to drug and biomarker assay sales.

Publications

10 25 50
 
Description Dr Katherine Finegan and Dr Sam Butterworth 
Organisation Manchester University
Country United States 
Sector Academic/University 
PI Contribution Provision of novel compounds for examination in assays.
Collaborator Contribution Characterisation of the effect of inhibitors in model systems and a broader understanding of target biology.
Impact Multi-disciplinary: pharmacology and medicinal chemistry.
Start Year 2017
 
Description Dr Simon Cook 
Organisation Babraham Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of small molecule inhibitors of a defined pathway for testing in cancer cell lines.
Collaborator Contribution Pathway knowledge, biological understanding, assay development, reagent generation.
Impact Increased understanding of a signalling pathway and the cellular response to pathway inhibition. Generation of a phospho-specific antibody to permit pathway biomarker work.
Start Year 2011
 
Title Pyrrolcarboxamide Derivatives For The Inhbition Of Erk5 
Description Small molecule inhibitors of ERK5 
IP Reference WO2016042341 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact Establishment of a collaboration with a Pharmaceutical Company