• Room 03.011 - CCRCB

    United Kingdom

Accepting PhD Students

PhD projects

My lab is open to medicinal chemistry and biochemistry PhD studentships applications. Research fields of interest include: - small molecule inhibitors - protease chemical biology - cancer - respiratory diseases - cystic fibrosis Previous research experience is desirable although not essential.

20022020

Research output per year

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Personal profile

Research Statement

Dr Rich Williams is an experienced medicinal chemist who has worked in both industry (Albany Molecular Research, Inc.) and academia (Vanderbilt University). In 2009, Rich Williams took up a post within the CCRCB as part of the fledging drug discovery group. During this time I have led the CCRCB Drug Discovery team, which has been involved in developing several projects in collaboration with various groups within Queen's. These included the Legumain project with Dr Paul Mullan (CCRCB), the development of a novel inhaled Cathepsin S inhibitor for the treatment of CF with Professors Scott, Taggart and Elborn. The Cathepsin S project has also involved working closely with industry. Past drug discovery successes included the development of BMS708163 a phase III clinical trial candidate for Alzheimer's disease, development and out-licensing of an mGluR5 positive allosteric modulator programme for the treatment of Schizophrenia. Dr Williams has also been involved in the development of several highly selective tool compounds for M1, mGluR4 PAMs and published several patents around novel and highly selective GlyT1 inhibitor. In the last 5 years, Dr Williams is well published and patented in the areas of drug design, hit to lead development, and lead optimisation.

Current Research - Protease Chemical Biology and Drug Design

Legumain - My lab has become very interest in the role of a cysteine protease, Legumain, in the progression of many humans cancers such as prostate, breast and ovarian. Research conducted here at Queen's in the labs of Dr Paul Mullan have revealed that Legumain plays a significant role in the proliferation and spread of cancer of these cancers as well as being a powerful predictive biomarker. Loss of this protease, in a number of cell line and in-vivo models, has revealed that cancer has a distinct addiction to Legumain which it requires for survival. Moreover, the loss of Legumain activity has no impact upon normal cell line function demonstrating that this protease is a viable drug target. My lab has been working on developing a potent, selective and cellularly active inhibitors of Legumain for study in in-vivo models. We have recently published several medicinal chemistry papers (Bioorganic Medicinal Chemistry Letters, 2014, 24, 2521-2524; Bioorganic Medicinal Chemistry Letters, 2015, 25, 5642-5645 and Bioorganic Medicinal Chemistry Letters, 2016, 26, 413-416) and conference presentations(IPS meeting 2015 (Malaysia), GTCBio conference ‘Proteases and their inhibitors’, San Diego, 2015; CRUK Accelerator Meeting, University of Leeds, Sept. 2017); detailing some of the early work and challenges in this area. This outreach has led to collaborations through access to our lead tool compounds being made available on request. In late 2017, we identified our first truly significant in-vivo compatible Legumain, QDD123427, details of which will be published in 2018.

Cathepsin S - CatS is a cysteine protease from the C1 family family of proteases of which there are eleven members; Cathepsins B, H, L, S, C, K, O, F, V, W and X. Each of these proteases have been reported to play a role in human physiology (Lalmanach, G. Clinic Rev Bone Miner Metab., 2011, 9, 148; Wilkinson, R.D., Williams, R., et al, Biological Chemistry, 2015, 396, 867). CatS, under normal physiological conditions, is confined to the endo/lysosomal lumen of antigen presenting cells and, along with CatL, plays a central role in MHC class II presentation. In the disease setting, CatS has been reported to be up-regulated in many human diseases, such as cancer, RA, acute lung injury, COPD and CF (Taggart, C.C., et al, Journal of Immunology, 2003, 171, 931). Within the context of disease, CatS has been shown to excreted in its active form (unique in the C1 class of proteases) and is a highly potent extracellular matrix (ECM) degrading protease. Of importance to this programme, CatS is also a more potent elastolytic protease that neutrophil elastase, which has been a major drug development target for decades. Additional downstream targets of CatS include laminin, fibronectin, proteoglycans and, of relevance to this programme, elastins, and the de-activation of anti-bacterial proteins (Rogan, M.P., et al, Journal of Infectous Diseases, 2004, 190, 1245; Martin, S.L., et al, Pediatric Pulmonary, 2010, 45, 860). Within the Drug Discovery lab, we are currently developing highly potent and selective CatS inhibitors, that can be delivered directly to the target organ via inhalation. Early studies in to test this hypothesis have been highly successful with low doses of our inhibitors having a significant impact on the hallmarks of inflammation.

Over the past three years we have been collaborating with Dr Brice Korkmax assessing the role of our CatS inhibitors on the maturation of CatC in models of respiratory diseases (Korkmaz, B. et al., J Biol. Chem., 2016, 291, 8486-8499).

CRUK Accelerator in Structural Biology – For the past 2 years I have been an active member of the Structural Biology network as the Belfast representative. This has led to the development of several active collaborations with leading academic groups within the UK. We are currently working with Professor Jane Endicott to further understand the functional binding of our lead Legumain inhibitors within the protease binding groove. To date, the only co-crystal structures generated have been with highly reactive covalent inhibitors which have provided limited structural information. In late 2017, Professor Endicott’s group were able to isloate their first series of crystals for further study with the aim of generating co-crystals with our optimised inhibitors later in 2018.

My lab is also collaboratoring with Dr Justin Bower (Beatson) and Professor Mark Carr (Leicester) on developing a novel inhibitors of an exciting epigenetic regulator of the CST6-Legumain pathway.

Research Interests

Drug Discovery

Protease Chemical Biology

Protease Inhibitors

Epigenetics

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Projects

Research Output

  • 38 Article
  • 1 Conference contribution
  • 1 Review article
  • 1 Other contribution

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

Haughey, C. M., Mukherjee, D., Steele, R. E., Popple, A., Dura-Perez, L., Pickard, A., Jain, S., Mullan, P. B., Williams, R., Oliveira, P., Buckley, N. E., Honeychurch, J., Williams, R., McDade, S., Illidge, T., Mills, I. G. & Eddie, S. L., 2020

Research output: Other contribution

Open Access
  • A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

    Wilkinson, R., Burden, R., McDowell, S., McArt, D., McQuaid, S., Bingham, V., Williams, R., Cox, O., O'Connor, R., McCabe, N., Kennedy, R., Buckley, N. E. & Scott, C., 28 Jun 2019, In : Journal of Oncology.

    Research output: Contribution to journalArticle

    Open Access
    File
  • 1 Citation (Scopus)
    91 Downloads (Pure)

    Application of nanotechnology to target and exploit tumour associated proteases

    Cogo, F., Williams, R., Burden, R. E. & Scott, C. J., 01 Nov 2019, In : Biochimie. 166, p. 112-131

    Research output: Contribution to journalReview article

  • 1 Citation (Scopus)

    Identification and SAR exploration of a novel series of Legumain inhibitors

    Eddie, S. L., Gregson, A., Graham, E., Burton, S., Harrison, T., Burden, R., Scott, C. J., Mullan, P. B. & Williams, R., 15 Jun 2019, In : Bioorganic & Medicinal Chemistry Letters. 29, 12, p. 1546-1548 3 p.

    Research output: Contribution to journalArticle

  • Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe

    Cogo, F., Smyth, P., Burden, R., Longley, D. B., Williams, R., Johnston, M., Poreba, M., Rut, W., Groborz, K., Salvesen, G., Drag, M. & Scott, C. J., 13 Dec 2018, In : Nanoscale - Royal Society of Chemistry.

    Research output: Contribution to journalArticle

    Open Access
    File
  • 1 Citation (Scopus)
    56 Downloads (Pure)

    Activities

    • 3 Publication peer-review
    • 1 Editorial activity

    Bioorganic and Medicinal Chemistry Letters (Journal)

    Richard Williams (Peer reviewer)

    30 Mar 2019

    Activity: Publication peer-review and editorial work typesPublication peer-review

    Journal of Medicinal Chemistry (Journal)

    Richard Williams (Peer reviewer)

    10 Jun 201615 Jan 2018

    Activity: Publication peer-review and editorial work typesEditorial activity

    Bioorganic and Medicinal Chemistry Letters (Journal)

    Richard Williams (Peer reviewer)

    01 Oct 201310 Jan 2018

    Activity: Publication peer-review and editorial work typesPublication peer-review

    Journal of Pharmacy and Pharmacology (Journal)

    Richard Williams (Peer reviewer)

    10 Feb 201210 Jan 2018

    Activity: Publication peer-review and editorial work typesPublication peer-review