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 (now Patrick G Johnston Centre for Cancer Research) as part of the fledging drug discovery group. During this time I have led the Drug Discovery team (from 2016), which has been involved in developing several projects in collaboration with various groups within Queen's. These included the Development of Legumain inhibitors for the Treatment of Poor Prognosis Prostate Cancer with Dr Paul Mullan (PGJCCR), the development of a novel inhaled Cathepsin S inhibitor for the treatment of CF with Professors Scott, Taggart and Elborn, and more recently the development of an inhlaed MPro Inhibitor with Professor Chris Scott and Marcin Drag (Wroclaw University of Science and Technology).

Past drug discovery successes included the development of BMS708163 a phase III clinical trial candidate for Alzheimer's disease, development and out-licensing of two drug dicovery programmes; mGluR5 positive allosteric modulators (J&J) and GlyT1 inhibitors 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 10 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).

MPro Inhibitor Project - From analysis of the COVID SARS viral genome was identified a series of cysteine proteases that were generated by the virus, which included 3CLpro, also known as MPro. Further studies revealed that this protease was involved in driving viral entry into host cells. To target this exciting protease, and thus reduce viral load, there was a significant effort around the development of novel MPro inhibitors. Despite years of research there is still a lack of clinically relevant inhibitors against this highly exciting protease. The aim of our project, much like the Cathepsin S programme, is to develop an MPro small molecule inhibitor that can be delivered directly to the lungs via inhalation. Our hypothesis is that direct target tissue delivery will greatly enhance the efficacy of the drug in lowering COVID SARS infection and therefore reduce the severity of the disease. This project is a collaborative programme and we are working with the one of the World leading expertise in protease chemical biology; Professor Marcin Drag. His group will be involved in screening the synthesized inhibitors and guiding the programme developmental pathway. 

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.

Drug Discovery

Protease Chemical Biology

Protease Inhibitors

Epigenetics