Development of small molecule inhibitors of the Orai1 channel as potential therapeutics for cardiovascular diseases
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
Ca2+ is involved in a wide range of cellular processes including signalling, mitochondrial regulation, motility and apoptosis. Orai1 is the pore-forming protein subunit of the calcium-release activated calcium (CRAC) channel, which was identified in 2006. This is a highly Ca2+-selective plasma membrane channel which refills the endoplasmic reticulum stores after depletion caused by a signalling event. This is known as store-operated calcium entry (SOCE) and is the main source of Ca2+ influx into non-excitable cells. Orai1 has been subject to considerable research regarding its structure, mode of action and clinical relevance. It plays a vital role in the mammalian immune system and has been proposed as a drug target in the areas of immunology, inflammatory disease and cancer, with other indications still emerging.
Unpublished research from the University of Leeds links Orai1 upregulation to pathological vascular smooth muscle cell remodelling, with the potential to target it as a therapeutic strategy. A novel series of Orai1 inhibitors was developed, with the lead compound being potent, selective and effective in vitro and in vivo. This PhD project expands upon this series of Orai1 inhibitors to improve potency and to better understand the structure-activity relationship of the compounds. Synthetic organic chemistry and computational methods are being used together to design and make structurally distinct compounds to improve upon ADME properties towards a more clinically suitable molecule. Literature Orai1 inhibitors have also been synthesised with the intent to develop chemical probes, which could be used for binding site elucidation and in biodistribution and imaging studies.
Unpublished research from the University of Leeds links Orai1 upregulation to pathological vascular smooth muscle cell remodelling, with the potential to target it as a therapeutic strategy. A novel series of Orai1 inhibitors was developed, with the lead compound being potent, selective and effective in vitro and in vivo. This PhD project expands upon this series of Orai1 inhibitors to improve potency and to better understand the structure-activity relationship of the compounds. Synthetic organic chemistry and computational methods are being used together to design and make structurally distinct compounds to improve upon ADME properties towards a more clinically suitable molecule. Literature Orai1 inhibitors have also been synthesised with the intent to develop chemical probes, which could be used for binding site elucidation and in biodistribution and imaging studies.
Organisations
People |
ORCID iD |
Richard Foster (Primary Supervisor) | |
Katherine Norman (Student) |
Publications
Bartoli F
(2020)
Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca2+ Handling After Pressure Overload.
in Circulation
Bartoli F
(2018)
Orai1 channels inhibition protects the heart from pressure overload-induced ventricular dysfunction
in Journal of Molecular and Cellular Cardiology
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013840/1 | 01/10/2016 | 30/09/2025 | |||
1799846 | Studentship | MR/N013840/1 | 01/10/2016 | 31/03/2020 | Katherine Norman |
Title | Library of novel Orai1 inhibitors |
Description | Library of novel synthesised compounds generated as potential Orai1 inhibitors. Most of these compounds have store-operated calcium entry inhibition data generated from a cell-based assay, selected compounds also have aqueous solubility and metabolic stability data acquired from a CRO. The structure of these compounds is currently confidential. Work on this library is ongoing. |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | No |
Impact | Further understanding of the structure-activity relationship of the Orai1 inhibitor template used at Leeds, which can be used to develop more drug-like compounds. |
Description | Late-breaker talk at a symposium on ion channels |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Short talk at an international conference on drug discovery on ion channels |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.rsc.org/events/detail/36598/6th-rsc-sci-ion-channels-as-therapeutic-targets-symposium |
Description | Poster presentation at 'Synthesis in Drug Discovery & Development' symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation at Concept Life Sciences 5th 'Synthesis in Drug Discovery & Development. Useful practice for further presentations and received some suggestions on methods to use. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.rsc.org/events/detail/33062/xii-biological-and-medicinal-chemistry-symposium-for-postgrad... |
Description | Poster presentation at Chemical Biology Meets Drug Discovery conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation at Chemical Biology Meets Drug Discovery conference at GSK, Stevenage. Useful presentation practice |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.rsc.org/events/detail/31598/chemical-biology-meets-drug-discovery-2018 |
Description | Poster presentation at MRC Knowledge Exchange Forum |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Networking event for MRC DiMeN students and relevant industrial and academic professionals |
Year(s) Of Engagement Activity | 2019 |
Description | Poster presentation at Mastering Med Chem IV |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Research poster presentation at Mastering Med Chem IV, Glasgow. Received some useful suggestions on further research plans. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.rsc.org/events/detail/28995/the-bmcs-mastering-medchem-iv-4th-rsc-bmcs-symposium-on-maste... |
Description | Poster presentation at NEPG conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Presented a poster on my research at the NEPG conference. Received some interest from other PG students but it was a largely biomedical conference and so the relevance of my work was limited (attendance and presentation at this event were mandated by my funding body). |
Year(s) Of Engagement Activity | 2017 |
URL | https://ne-pg.co.uk/ |
Description | Poster presentation at departmental postgraduate conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at an internal chemistry postgraduate conference. Useful practice for further external poster sessions. |
Year(s) Of Engagement Activity | 2018 |
Description | Poster presentation at the Astbury Away Day (internal) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at an Astbury centre away day. Got useful feedback from other Leeds researchers in a variety of different fields and had ideas for further work. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.astbury.leeds.ac.uk/research/retreats.php |
Description | Research update talk at an internal departmental retreat |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Gave a 10 minute talk on my research to other members of my group and a related research group at an internal retreat. Other researchers asked questions and provided suggestions, and I gave advice on a method I have used to another researcher. |
Year(s) Of Engagement Activity | 2019 |
Description | Research update talk at an internal departmental retreat |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | 10 minute research update talk as detailed previously. Received helpful suggestions on further directions for my work. |
Year(s) Of Engagement Activity | 2018 |
Description | Talk at internal cardiovascular research retreat |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Talk at an internal research retreat in cardiovascular research - a broader range of scientists than the previous retreats |
Year(s) Of Engagement Activity | 2019 |
Description | Talk at internal chemistry postgraduate conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | 25 minute talk on my research at an internal department postgraduate conference |
Year(s) Of Engagement Activity | 2019 |