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.
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.
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.
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.
Organisations
- University of Strathclyde (Lead Research Organisation)
- University of Sheffield (Collaboration)
- Cornell University (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- QUEEN'S UNIVERSITY BELFAST (Collaboration)
- Beatson Institute for Cancer Research (Collaboration)
- Cancer Research UK Beatson Institute (Project Partner)
- University of Glasgow (Project Partner)
- Newcastle University (Project Partner)
- Mayo Clinic (Project Partner)
- University of California, San Diego (Project Partner)
- Cancer Research UK Technology (Project Partner)
Publications
Description | Development of a first-in-class preclinical IKKalpha inhibitor for the treatment of castrate resistant prostate cancer |
Amount | £553,255 (GBP) |
Funding ID | RIA18-ST2-013 |
Organisation | Prostate Cancer UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2020 |
End | 12/2023 |
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 | Academic/University |
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 | Investigating IKKalpha's role in histone phosphorylation |
Organisation | Cornell University |
Department | Weill Cornell Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | Provide proprietary IKKalpha inhibitors for the Josefowicz lab to interrogate histone phosphorylation mechanisms |
Collaborator Contribution | Collaboration with Steven Z. Josefowicz and Alexia Martínez de Paz, Weill Cornell Medicine Our studies on "signaling-to-chromatin" have uncovered two dedicated pathways involving the phosphorylation of histones, and demonstrate their potency to reorganize chromatin and stimulate transcription of signal responsive genes (Josefowicz, Mol Cell 2016; Armache, Nature 2020). One pathway involves the I-Kappa-B kinase alpha (IKKa) that co-transcriptionally phosphorylates S31 at the histone protein H3.3 (H3.3S31ph), which in turn ejects transcriptional co-repressors and stimulates catalytic activity of important chromatin regulators to enable a rapid and robust transcription. Our collaboration with Professor Simon MacKay and University of Strathclyde is aimed to test their newly developed IKKa inhibitors in our bone marrow derived macrophage (BMDM) system and other contexts such as B-cell development and lymphomagenesis. Our initial experiments have served to validate the efficacy of IKKa inhibitors in decreasing phosphorylation of H3.3S31 and gene expression after bacterial lipopolysaccharide (LPS) stimulation of BMDMs, and corroborate our previous experiments using specific short-hairpins targeting IKKa (Armache, Nature 2020) (Figure 1 A, B). Furthermore, our preliminary data show that interferon gamma (IFNg)-response genes (IRGs) are downregulated upon pre-treatment with IKKa inhibitor and phosphorylation of H3.3S31 at those genes is decreased (Figure 1 C, D). These data suggest that IKKa is co-opted downstream of the IFNg receptor (that it is not known to engage the NFkB signaling pathways) to phosphorylate H3.3S31 and stimulate transcription of IRGs in macrophages. |
Impact | No publications as yet - compounds still being used to explore. Results look very interesting. |
Start Year | 2021 |
Description | Mark Pritchard, University of Liverpool |
Organisation | University of Liverpool |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are supplying our IKKalpha inhibitors to the group |
Collaborator Contribution | Mark is investigating the effects of our IKKalpha inhibitors in inflammatory bowel diseases |
Impact | Data still being generated |
Start Year | 2019 |
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 |