First-in-class Selective IKKalpha Inhibitors for the Treatment of Castrate Resistant Prostate Cancer (CRPC) and Pancreatic Cancer

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

Despite real progress being made in the treatment of many cancers, there are still significant issues to overcome, particularly for patients who have become resistant to treatment, or where the cancer has spread beyond the original tumour. This is particularly true of prostate cancer, which is the most common cancer in men in the UK.
There are 36,000 new cases of prostate cancer diagnosed every year in the UK and this figure is predicted to double over the next 20 years.
Whilst there are treatments available for early-stage prostate cancer (cancer that is still confined to the prostate cancer), some men become resistant to treatment and the cancer progresses and spreads (metastasizes). This type of prostate cancer is called castrate resistant prostate cancer (CRPC) and current treatments can only extend life expectancy by up to 9 months. New medicines to treat this disease are therefore urgently needed.
We have discovered a new way to treat CRPC. We have shown that there are high levels of a protein called IKKalpha in the tumours of men who had shorter time to death. We and our Project Partners have also shown that this same protein is involved in the progression from early-stage prostate cancer to CRPC. We believe that a drug which stops this protein from functioning will prevent CRPC from developing and increase life expectancy by up to 3 years.
Evidence is also emerging that this IKKalpha protein also plays a role in pancreatic cancer, which is currently incurable.
We are the only group to have developed compounds that stop this protein from functioning, without also stopping closely-related proteins from functioning (and resulting in unwanted side-effects).
We have also demonstrated that our compounds, when added to prostate cancer cell samples in a laboratory environment, slow their growth and cause them to die. However, these compounds require further development and are not yet suitable as medicines for CRPC. For example, they are broken down in the body too quickly to exert their effects in a patient and they are also not very water-soluble, which would make them difficult to administer. The aim of this project is to design compounds with better properties (a process called lead optimisation).
We will then be able to determine whether our optimised compounds stop IKKalpha from functioning and stop cancers growing and spreading in mice, without adverse or toxic effects. This is essential to demonstrate before testing in humans.
This project involves medicinal chemists, biologists, clinicians and technology transfer professionals working together as a team to achieve the goal of effective new medicines for patients with CRPC and pancreatic cancer.

Technical Summary

This proposal aims to identify two advanced lead compounds suitable for full preclinical evaluation as candidate drugs to treat patients with castrate resistant prostate cancer (CRPC) and potentially pancreatic cancer (PanC). Over the past 15 years, compelling evidence from several research groups has demonstrated that intracellular signalling involving constitutive activation of IKKalpha and the non-canonical NFkappaB pathway plays a key role in the progression of hormone-dependent prostate cancer to CRPC. In a retrospective analysis employing clinical CRPC specimens, we observed that patients with tumours expressing high levels of nuclear IKKalpha and RelB (a key biomarker of the noncanonical pathway) had a significantly worse prognosis than those with low expression. Studies by ourselves and others also demonstrated that IKKalpha and the non-canonical NFkappaB pathway have a role in other malignancies including pancreatic and haematological cancers.
Through extensive prior work, we are the only group to have developed a series of low nanomolar-potent, highly isoform selective IKKalpha inhibitors that could have clinical applications in CRPC, and potentially PanC. We have shown that it is possible both to improve the physicochemical and PK profile of our compounds while simultaneously abrogating off-target kinase activity and maintaining IKKalpha potency and selectivity over IKKbeta. We have a comprehensive assay cascade in place that includes validated primary cellular PD readouts that demonstrate target engagement for IKKalpha (e.g. p100 phosphorylation and RelB translocation) and for IKKbeta (IkappaB degradation) to enable selectivity assessment in the physiological context. We have also identified secondary downstream markers to provide orthogonal confirmation of target engagement that can be translated into in vivo models to test the efficacy of compounds emerging from optimisation of our currently most promising lead series and from a back-up series.

Planned Impact

There are several broad categories of beneficiaries from this research. Foremost, are the patients that we hope will ultimately benefit from our new approach to treatment - we are aiming to identify two advance lead compounds suitable for preclinical development to treat patients with castrate resistant prostate cancer (CRPC) and potentially pancreatic cancer (PanC). Current therapies for CRPC are severely limited and for pancreatic cancer, are non-existent. We hope to achieve societal benefit by providing more effective treatments - specifically increasing survival times from 3-9 months to 2-3 years and enhancing the quality of life for CRPC and PanC patients and their carers and dependants.
There are 36,000 new cases of prostate cancer reported every year and this figure is predicted to double over the next 20 years. As CRPC is currently a major complication arising in 80% of patients, even with existing therapies, this will place a considerable strain on the healthcare sector. For pancreatic, it is essentially untreatable because the 9,000 cases that arise annually present with locally advanced or metastatic disease. More effective treatments will therefore achieve economic benefit for healthcare providers and employers by reducing hospital admissions and the costs of palliative and end of life care. Furthermore, the candidate drugs themselves are expected to be more cost-effective than current immunological-based therapies.
We anticipate that a pharmaceutical company partner will benefit from in-licensing this opportunity as this will add first-in-class agents to their pipeline and identify a new patient group that can benefit from their medicines. Ultimately, this provides economic benefit to that company through increased revenues. Cancer Research UK, Prostate Cancer UK and the University also benefit from a share of those revenues and will channel these funds into further research for continued societal benefit.
Once IP protection and the appropriate agreements are in place, our library of compounds, with selectivity ratios for IKKalpha against IKKbeta in the range 1:1 to 1:200, will provide a unique resource of immense benefit to academic and clinical researchers working in the NFkappaB field. Our compounds can be used to explore other disease scenarios linked with IKKalpha such as haematological malignancies, glioblastoma, naso-pharyngeal carcinoma, breast subtypes and colorectal cancers; inflammatory diseases such as rheumatoid arthritis, asthma and COPD and in cardiovascular and neurological diseases.
The team will also contribute to the benefits that arise from public engagement with cancer research by providing material for Cancer Research UK's targeted-giving site - members of the public have already donated £196,800 to the project and by continuing to be involved in the public-science open days organised by CRUK throughout Scotland to make the charity's volunteers aware of the importance of their activities in raising funds for research.

Publications

10 25 50
 
Title IKKa selective compound library 
Description A unique library of over 600 compounds with varying degrees of selectivity and potency for IKKa over IKKb. Once patented this will be a unique resource for all researchers interested in targeting IKKa in a variety of clinical scenarios. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Enabled international collaboration around the project, thus bringing in partners with a world class reputation. This is a first in class drug category and as such its development has impact in the IKKa and NFkB field. The sharing of the library and specific compounds has allowed research into the targeting of the IKKa pathway in other cancers. All compounds have been supplied with appropriate MTAs in place. 
 
Title Recombinant IKK proteins 
Description Over-expression vectors in baculovirus systems to enable generation of recombinant IKKa and IKKb proteins for use in co-crystallization studies with compounds from our libraries. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact solving the co-crystal structure will help optimise potency of compounds for IKKa over IKKb. 
 
Title The first class of potent and selective IKKalpha inhibitors 
Description SU1644 and SU1433 are first-in-class IKKalpha inhibitors that can be used to interpret NFkappaB-dependent and independent pathways controlled by this kinase 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Under MTA, collaborators are generating more data for future funding applications 
 
Title biomarkers for the IKKa pathway 
Description Characterisation of pharmacodynamic readouts for IKKa and IKKb target engagement with the view to translation into in vivo models. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Too early as these are just being validated. This will however open up the field of IKKa research allowing validation of target engagement and enable manipulation of the pathway to be assessed and applied to disease states. 
 
Title development of a novel high throughput biochemical assay for IKKa 
Description there was no suitable commercially available assay for IKKa when we started so we set up the assay based on the IKKB kit consumables from Cell Signaling. We have implemented a robust, reproducible, cost-effective DELFIA assay, using readily available biotinylated-I?Ba as a substrate to determine potential IKKa inhibitors from the focused medicinal chemistry library. This allows assays the determination of both IKKa and IKKß inhibition simultaneously. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Acts as the primary assay in the full assay cascade for compound optimisation. 
 
Description Aymen Idris, University of Sheffield, UK 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution We supplied the compounds to Sheffield for assessment
Collaborator Contribution Compounds have been assessed in in vitro and in vivo models of bone metastasis in advanced prostate cancer
Impact awaiting results
Start Year 2016
 
Description Danny Huang, Beatson Institute 
Organisation Beatson Institute for Cancer Research
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We supply compounds for crystallography
Collaborator Contribution Xray crystallography
Impact Awaiting results
Start Year 2015
 
Description David Waugh, QUB Belfast 
Organisation Queen's University Belfast
Country United Kingdom 
Sector Academic/University 
PI Contribution We will supply the compounds to Sheffield for assessment and one of the post doc. on the team will conduct the experiment at QUB
Collaborator Contribution Compounds to be assessed in syngeneic mouse models of prostate cancer
Impact Experiments not started yet
Start Year 2016
 
Description Michael Karin-UC San- Diego 
Organisation University of California, San Diego (UCSD)
Country United States 
Sector Academic/University 
PI Contribution Provision of IKKa specific compounds have been sought after by the community for many years in particularly the Karin group who are the world leaders in IKKa in prostate cancer. We have provided compounds and now have a MTA and collaborative agreement to work together in realizing their clinical potential. This is a major boon for the project. We share information to allow progression of each project.
Collaborator Contribution as above- mutuall partnership undertaking experiments and sharing data
Impact none yet
Start Year 2015
 
Description Peter Storz, Mayo Clinic, Florida USA 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution We supplied the compounds to Mayo for assessment
Collaborator Contribution Compounds have been assessed in vitro and in vivo models of pancreatitis
Impact Awaiting results
Start Year 2015
 
Description Philip Cohen, University of Dundee 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution Compounds are being assessed by Philip Cohen's group
Collaborator Contribution Compounds are being assessed against TRAF signalling pathway
Impact Awaiting results
Start Year 2015
 
Description The challenges of anticancer drug discovery: Biggar Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Invited lecture to stimulate debate
Year(s) Of Engagement Activity 2018