INNTREST's Achievements to inspire you to work with us.

  • Gene therapy

    Global project lead for the early and late clinical development of gene therapy for rare orphan diseases Sanfilippo B and Huntington's disease.

    Gene therapy is the use of genes as treatment for a genetic disease by directing the expression of a therapeutic protein or restoring the expression of a missing protein. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual to repair a faulty gene copy or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. This approach is different from traditional drug-based approaches, which may treat symptoms but not the underlying genetic problems. The scope of this approach is broad and promising for a wide number of diseases including inherited disorders, some types of cancer, and certain serious viral infections.

  • Next generation antibiotics (I)

    Drug Discovery Team Leader directing the search for the next generation antibacterial and antifungal compounds with a special focus on the inhibition of microbial metalloenzymes. In this drug discovery program, high-throughput screening of newly identified metalloenzyme targets was combined with phenotypic screening of pathogenic bacteria and fungi. Validated screening hits with tractable chemistry and potential for obtaining a strong IP position were further developed by a focused Hit-2-Lead optimization process.

    More than 10 screening campaigns were performed with different success rates. Two subsequent Hit-2-Lead programs led to the discovery of proprietary new chemical series that show high potency against multi-resistant gram-positive bacteria like Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant enterococci (VRE) as well as gram-negative pathogens such as Pseudomonas aeruginosa.

  • Plant medicines

    Commissioned by the Center of Expertise for Plant Compounds ('Kenniscentrum Plantenstoffen', KCP), INNTREST reviewed the multitude of compounds of plant origins which are used by the pharmaceutical industry to produce medicines. On the basis of this inventory, opportunities were defined to pilot a number of programs aimed at the controlled greenhouse cultivation of these plants and extraction of the relevant high-value compounds.

    Plants have played a dominant role in the development of traditional Chinese medicine and the Indian Ayurveda but also in the modern Western medicine and healthcare. The basis of the healing properties of plants lie in the production of specific chemicals or phytochemicals by plants. These plant compounds are often secondary metabolites which are being produced under stress conditions to provide protection against, for example, insects or extreme weather conditions. The amounts of the phytochemicals are strongly dependent on among others plant origin, growing conditions and age. As a result medicinal use of (dried) plant preparations and extracts is often a game of 'Trial and Error'.

  • COILED

    Founder of Center for Open Innovation in Lead Discovery (COILED), a public private partnership with a mission to provide a de-risked drug discovery platform and medicinal chemistry infrastructure to translate breakthrough (academic) research into drug candidates suited for clinical studies. Together with project partners Radboud University Nijmegen, Radboud University Medical Center, Pivot Park Screening Centre, BioAxis Research and Pansynth, 4.4 M€ start-up financing from EFRO was obtained in 2016. Focus of COILED is the groundbreaking research by Professor Mihai Netea (Spinoza laureate 2016) into the discovery that the innate immune system of mammals, including human beings, can be 'trained'.

    With big pharma exiting the early stages of pharmaceutical R&D, drug discovery centers like COILED are poised to take center stage as evidenced by the successes of, for instance, VanderBilt Center for Neuroscience Drug Discovery, Nashville, TN.

    EFRO logo

  • bqure bone therapeutics

    Co-founded bqure, to focus on the discovery and development of innovative small molecule therapeutics for bone fracture healing. The business model was based on achieving Proof-of-Concept (PoC) with exit possibilities upon finalizing Phase 2 clinical studies within 4 years. The strategy centered on the in-licensing of two clinical candidates that showed favorable Phase 1 clinical safety data for repositioning to fracture healing.

    Worldwide, around 9 million new fractures are reported but there is a rapid increase due to an aging population (up to 5-fold in 2050). The costs in Europe for osteoporotic fractures are expected to increase from 36 billion in 2005 up to 54 billion EUR by 2025. Fractures in the elderly and bone cancer patients lead to a major, often irreversible loss of quality-of-life and are associated with an increase in morbidity and mortality. 5-20% of fractures result in delayed or impaired (non-union) healing, with no or limited therapies available to improve and accelerate fracture healing. Currently, there is no standard-of-care available for fracture healing.

  • Next generation antibiotics (II)

    Liaison and project leader of strategic partnership between British Biotech (Oxford, UK) and DeNovo Pharmaceuticals (Cambridge, UK), which focused on the identification of new drug leads using structure-based drug design (SBDD). As part of this program new crystal structures of bacterial peptide deformylase-inhibitor complexes were solved and with the help of SBDD novel inhibitors were designed and patents filed.

    The metalloenzyme peptide deformylase (PDF) represents one of the most promising bacterial targets in the search for the next generation antibiotics with a novel mode-of-action that lack cross-resistance to existing drugs. Initial research and clinical development focused on anti-pneumococcal applications. As part of British Biotech's antibiotic program, BB-83698 was selected as a First-in-Class clinical candidate with high in vitro potency and in vivo efficacy in preclinical animal models of Streptococcus pneumoniae infection. In first in man studies, the inhibitor was administered by intravenous infusion and was shown to exhibit generally dose-proportional pharmacokinetics. It was well tolerated up to doses providing predicted therapeutic exposures.

  • Griffin Discoveries

    As Chief Scientific Officer of Griffin Discoveries led efforts to transition academic spin-off towards a fully operational pharmaceutical SME. Conducted strategic review and established strong value proposition focused on its lead program on dual histamine receptor antagonists. Led (venture) capital raising activities to conduct (pre)clinical development of GD136 and follow-up program for treatment of allergic diseases including ocular allergy, allergic rhinitis and atopic dermatitis. Secured an initial 100 k€ PoC grant From VU Amsterdam.

    Griffin Discoveries was founded in 2009, to capitalize on the 40-year track-record in G-protein coupled receptor (GPCR) research of the medicinal chemistry group from VU University Amsterdam currently headed by Professor Rob Leurs. The company is widely acknowledged for its expertise in the discovery and development of small-molecule drugs that target histamine receptors. It operates a hybrid business model based on achieving clinical Proof-of-Concept for in-house projects like GD136 and leverage of its histamine GPCR drug discovery platform.

  • New osteoporosis treatment

    Project leader odanacatib Best-in-Class (BiC) follow-up program. Led the technology transfer from Merck Frosst in Montreal, Canada, to R&D site in the Netherlands, defined BiC deliverables and compound attributes, directed medicinal chemistry team (+20 FTEs). Focus of the program was to select new drug candidates that combine the favorable attributes of odanacatib with improved clinical outcomes.

    Odanacatib, MK-0822, is an investigational treatment for osteoporosis and bone metastasis. It is an inhibitor of cathepsin K, an enzyme involved in bone resorption, with a unique covalent reversible binding mode. The Phase III clinical trial for this compound was stopped early after a review showed it was highly effective and had a good safety profile. In 2016, Merck decided to discontinue development after an independent analysis of adverse cardiovascular events confirmed an increased risk of stroke. Odanacatib was predicted to generate a billion USD per year in sales by 2020.

  • Drug lead optimization

    Head of Lead Optimization department and Project Leader directing the optimization and selection of drug candidates for clinical evaluation in humans. Projects focused on selecting inhibitors for specific molecular targets such as proteases, kinases and G-protein coupled receptors implicated for use in treatment of cancer, bacterial infections and particularly auto-immune and inflammatory diseases like psoriasis, multiple sclerosis and rheumatoid arthritis.

    Lead optimization is a process in which medicinal chemistry-driven optimization of the biological and physicochemical properties of bioactive molecules is achieved through selective structural modifications. Well organized and timely conducted iterative cycles of design, synthesis and biological testing provide the basis for successful drug optimization campaigns. Championing the multidisciplinarity of this game will guide the selection of compounds that fulfill all in vitro and in vivo criteria for further pre-clinical and clinical evaluation.

  • Ocular allergy

    Project leader dual histamine receptor project focused on the pre-clinical development of a First-in-Class treatment of ocular allergy and symptoms related to it, specifically the occurrence of 'red eyes' caused by swollen or dilated blood vessels on the sclera, the white outer surface of the eye. Directed toxicological evaluation and CMC activities. Prepared comprehensive technology appreciation report, including animal pharmacology data, as part of due diligence package and to enable IND filing.

    Lead candidate for pre-clinical and subsequent clinical development is GD136 which showed antagonistic histamine 1 receptor (H1R) and histamine 4 receptor (H4R) activities. As a result of this dual mode-of-action, GD136 presents both an anti-allergic and anti-inflammatory mode-of-action that can treat acute as well as chronic forms of ocular allergy. GD136 successfully completed a preliminary safety evaluation and demonstrated superior efficacy to steroids and olopatadine (the industry’s 'gold standard' drug) in an established pre-clinical model of ocular allergy.

  • Discovery of acalabrutinib

    Initiator of BTK (Bruton tyrosine kinase) drug discovery program and discoverer of key selectivity element of acalabrutinib. The BTK project was started as a spin-off of an ongoing project focusing on a kinase with large structural similarities to BTK. Through selective modification of earlier identified inhibitors we were able to skew the activity towards a fully selective BTK profile. Further optimization led to the identification and selection of irreversible BTK inhibitor acalabrutinib for the treatment of cancer and immunological disorders.

    Acalabrutinib is being developed by Acerta in Oss, The Netherlands. Currently, Phase III trials for B-cell blood cancers, e.g. relapsed chronic lymphocytic leukemia, and Phase I/II studies in multiple solid tumors are ongoing. In December 2015, Acerta was acquired by AstraZeneca in a multibillion dollar deal. Acalabrutinib has potential peak-year sales in excess of $5 billion worldwide.

  • Metalloenzyme library generation

    Combinatorial chemistry team leader establishing a proprietary, focused metalloenzyme library, compound logistics and data base generation. Library construction involved design of new chemotypes, scouting new synthetic routes and procedures, parallel synthesis, automated purification and analysis. All library compounds feature a 'chelator' moiety for metal binding and a peptidomimetic or heterocyclic scaffold.

    Metalloenzymes catalyze a wide variety of reactions with high efficiency, selectivity and under mild conditions, by combining the powerful reactivities of metal ions with the exquisite control of electronic and steric properties achievable with proteins. These catalysts perform vital reactions in biochemical processes such as photosynthesis, respiration, and natural product biosynthesis and metabolism. Metalloenzyme have provided a rich avenue for developing drugs as evidenced by multibillion selling angiotensin converting enzyme (ACE) inhibitor captopril for the treatment of arterial hypertension and cardiovascular diseases.

  • Orphan drug development

    Global project lead for the early and late clinical development of gene therapy for rare orphan diseases Huntington's disease and Sanfilippo B.

    Huntington’s disease is a slowly progressive autosomal neurodegenerative disorder characterized by the development of abnormalities in movement, cognitive decline and behavioral disturbances. It is caused by a mutation in either one of an individual's two copies of a gene called Huntingtin. Sanfilippo B is an autosomal recessive lysosomal storage disease, which is caused by a deficiency in one of the enzymes needed to break down the glycosaminoglycan heparan sulfate. In both disorders, progressive neurodegeneration deteriorates a person’s physical and mental abilities eventually leading to death. However, while Sanfilippo B affects very young children, onset of disease symptoms for Huntington’s typically occur around midlife. There are currently no cures for Sanfilippo B and Huntington’s disease.

  • Horticultural business concepts

    Developing innovative projects and business concepts for the Dutch horticultural industry, based on exploiting the bioactivity of unique bioactive compounds produced by plants but also defined plant extracts. By request of the Center of Expertise for Plant Compounds ('Kenniscentrum Plantenstoffen', KCP), focus was specifically directed towards so-called secondary plant metabolites that may be used as ingredients in cosmetics, pharmaceuticals, agrochemicals and as food or feed additives.

    Projects being developed included the use of naturally occurring sesquiterpenes and extracts thereof for use as a green insecticide for crop protection, CBD for the treatment of rare forms of childhood epilepsy, controlled pharmaceutical production of diterpenoids for treating actinic keratosis, and isolation of steroid amines from tomato plant residual waste streams and conversion into high value steroids.

  • Kinase cross-screening platform

    As T-cell kinase drug discovery project leader set-up a kinase cross-screening platform to accelerate the hit generation process for kinases of interest and enable serendipity. The big advantage of cross-screening is the high hit rates due to the high similarity of the ATP binding site between kinases.

    Compounds from the T-cell kinase and other kinase projects were combined with compounds from the company’s proprietary collection queried for ATP binding features. Further, the library was enriched with compounds from external commercial collections and commercially available kinase inhibitors as well as compounds from ongoing kinase drug discovery projects. High and medium throughput screening provided starting point for a range of kinase targets such as Jnk1, Jnk2, Src, BRAF and MEK, some of which led to successful lead optimization programs.

    Today, the cross-screening paradigm in which selective inhibitors from one protein target family are screened against other family members is being used throughout the pharmaceutical industry.