Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases).

An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in theirCTSC gene, resulting in the complete absence of CatC activity.

Towards imaging the immune state of cancer by PET: Targeting legumain with C-labeled P1-Asn peptidomimetics carrying a cyano-warhead.

Purpose: M2-type tumor-associated macrophages (TAM) residing in the tumor microenvironment (TME) have been linked to tumor invasiveness, metastasis and poor prognosis. M2 TAMs suppress T cell activation, silencing the recognition of the cancer by the immune system. Targeting TAMs in anti-cancer therapy may support the immune system and immune-checkpoint inhibitor therapies to fight the cancer cells.

Cathepsin S (CTSS) activity in health and disease - A treasure trove of untapped clinical potential.

Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted expression profile, inducible upregulation and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome, degrading unwanted and damaged proteins, it has increasingly been shown to mediate a number of distinct, more selective roles including antigen processing and antigen presentation, and cleavage of substrates both intra and extracellularly. Increasingly, aberrant CTSS expression has been demonstrated in a variety of conditions and disease states, marking it out as both a biomarker and potential therapeutic target.

TBX2 acts as a potent transcriptional silencer of tumour suppressor genes through interaction with the CoREST complex to sustain the proliferation of breast cancers.

Chromosome 17q23 amplification occurs in 20% of primary breast tumours and is associated with poor outcome. The TBX2 gene is located on 17q23 and is often over-expressed in this breast tumour subset. TBX2 is an anti-senescence gene, promoting cell growth and survival through repression of Tumour Suppressor Genes (TSGs), such as NDRG1 and CST6.

Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer.

The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa.

Application of nanotechnology to target and exploit tumour associated proteases.

Proteases are hydrolytic enzymes fundamental for a variety of physiological processes, but the loss of their regulation leads to aberrant functions that promote onset and progression of many diseases including cancer. Proteases have been implicated in almost every hallmark of cancer and whilst widely investigated for tumour therapy, clinical adoption of protease inhibitors as drugs remains a challenge due to issues such as off-target toxicity and inability to achieve therapeutic doses at the disease site. Now, nanotechnology-based solutions and strategies are emerging to circumvent these issues.

Identification and SAR exploration of a novel series of Legumain inhibitors.

This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.

Police-community safety and trust.

(1)In 2017 alone, 46 states have enacted over 270 laws affecting policing. (2) At least six states have enacted laws to train the public on their rights and expectations during police interactions. (3) Police are increasingly partnering with health care professionals to more safely respond to mental health and substance use disorders.

A bioavailable cathepsin S nitrile inhibitor abrogates tumor development.

Background: Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models.

Simulating social-ecological systems: the Island Digital Ecosystem Avatars (IDEA) consortium.

Systems biology promises to revolutionize medicine, yet human wellbeing is also inherently linked to healthy societies and environments (sustainability). The IDEA Consortium is a systems ecology open science initiative to conduct the basic scientific research needed to build use-oriented simulations (avatars) of entire social-ecological systems. Islands are the most scientifically tractable places for these studies and we begin with one of the best known: Moorea, French Polynesia.

Flat SAR of P3-methylsulphonamide based small molecule legumain inhibitors.

This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat.

Development of a potent and selective cell penetrant Legumain inhibitor.

This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.

CCL2 is transcriptionally controlled by the lysosomal protease cathepsin S in a CD74-dependent manner.

Cathepsins S (CatS) has been implicated in numerous tumourigenic processes and here we document for the first time its involvement in CCL2 regulation within the tumour microenvironment. Analysis of syngeneic tumours highlighted reduced infiltrating macrophages in CatS depleted tumours. Interrogation of tumours and serum revealed genetic ablation of CatS leads to the depletion of several pro-inflammatory chemokines, most notably, CCL2.

Cathepsin S: therapeutic, diagnostic, and prognostic potential.

Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain.

P3 SAR exploration of biphenyl carbamate based Legumain inhibitors.

This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub-nanomolar inhibitor of Legumain.

Modeling the building blocks of biodiversity.

Background: Networks of single interaction types, such as plant-pollinator mutualisms, are biodiversity's "building blocks". Yet, the structure of mutualistic and antagonistic networks differs, leaving no unified modeling framework across biodiversity's component pieces.

Methods/principal Findings: We use a one-dimensional "niche model" to predict antagonistic and mutualistic species interactions, finding that accuracy decreases with the size of the network.