KINETO Lab

Research&Development

drug development

NEW COMPOUNDS GIVE

A NEW HOPE

KINETO Lab has extensive expertise and substantial experience in designing experiments to be used along the preclinical drug discovery pipeline for successful and effective research and development of anticancer drugs bringing candidates to the clinical stage faster.

KRAS mutations targeting consortium

DEVELOPMENT OF TARGETED THERAPIES AGAINST HUMAN TUMORS HARBORING MUTATIONS OF KRAS ONCOGENE

Grant: FUTURE-2021

2021-2024

In this project, KINETO Lab Ltd. continued development of KRAS targeting small molecules on tumor cells carrying different KRAS mutations (G12C, D, V) on in vitro and in vivo tumor models.

Moreover, optimization of KRAS inhibitors identified from a fragment-based molecular library will be performed for therapy efficacy improvement.

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One of the biggest health problems in the developing world is that the mortality rate of chronic, non-communicable diseases has increased in parallel with the increase in life expectancy, so the care of cancer diseases is also an increasing problem for health care systems. In Hungary, too, cancer mortality has gradually increased over the past 60 years. Two-thirds of cancer cases occur over the age of 60, and unfortunately approximately 70,000 people are diagnosed with malignant tumor yearly. Today, the use of chemotherapeutics, which are used to inhibit rapidly dividing cells – such as tumor cells – has not yet been displaced from the therapy of human cancer diseases, but personalized targeted therapy and the use of molecules with biological effects are increasingly coming to the fore. With their gradual spread, the survival (recovery) of cancer patients increases significantly, and the patients’ quality of life (symptom-free period) improves, where the social usefulness of which is important to emphasize.

The division and differentiation of the approximately 37 billion cells in the human body are regulated in many cases by signal pathways operating through receptor tyrosine kinases. The most important regulators of these signaling pathways are the GTP-binding RAS proteins, which are mutated in human tumors, but especially in lung, colon and pancreatic cancer. In such cases, the cells break away from the physiological regulation dependent on growth factors and begin to divide indefinitely, and then a tumor may develop. Recently, the investigation of mutant RAS proteins has become a key issue in oncology, because the presence of the KRAS mutation is one of the main causes of resistance to classical chemotherapeutics and new targeted molecular therapy drugs.

The consortium plans are to identify effective inhibitors for the inhibition of mutant KRAS proteins, based on partly already known and partly still to be determined 3D spatial structure information, using the most modern fragment-based molecular design method. The biochemical and antitumor effects of the synthesized potential inhibitors will be tested on in vitro and in vivo models of human tumors and then selected according to their effectiveness. The second objective of the project is to identify and develop effective inhibitors that affect the newly discovered tyrosine regulatory pathway of the KRAS protein by keeping the active, GTP-bound RAS in a phosphorylated state, i.e. inactivating it. As the third goal of the project, we intend to use allele-specific covalent inhibitors in combination with active substances. These compounds alone have not previously been shown to be effective, however, recent data suggest that combination therapy may be beneficial in certain oncogenic RAS-expressing tumors.

The Consortium is led by the Natural Science Research Center, its members are Semmelweis University, Eötvös Loránd University of Science and KINETO Lab Ltd.

The Consortium competes with the best international research groups because we believe that, based on our research experience, we are capable of designing, synthesizing and screening compounds that inhibit oncogenic KRAS using the most modern innovative methods.

HORIZON 2020 – EUROPEAN TRAINING NETWORK: MAGICBULLET::RELOADED

SMALL MOLECULE DRUG CONJUGATES FOR TARGETED DELIVERY IN TUMOR THERAPY

Grant: MAGICBULLET::RELOADED under the Marie Skłodowska-Curie grant agreement No 861316

2020-2023

KINETO Lab Ltd. continued its membership in the ”MAGICBULLET::RELOADED” international research consortium as extension from „MAGICBULLET” built for studying the application of small molecule and peptide drug conjugates for targeted tumor therapy.

The ETN Magicbullet::Reloaded will expand the field of investigation from peptide-drug conjugates (PDCs) to small molecule-drug conjugates (SMDCs) with a special focus on drugs capable to stimulate tumor immune responses and overcome resistance to immune-therapy.

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Despite the continuing development of new and more efficient treatments, cancer remains the second cause of premature death worldwide. Multi-faceted interdisciplinary research efforts in industry and academia on different aspects of cancer have provided a knowledge basis for the development of novel therapeutic approaches. An ideal therapeutic agent would be a “magic bullet” that only kills the target cells. This ETN initiative with the title Magicbullet::Reloaded refers to Ehrlich’s bold idea and builds on the previous experience of the ETN MAGICBULLET (2015-2018, grant agreement No. 642004).

The consortium has been substantially expanded to perfectly address the needs of the new research direction. The planned ETN will design and synthesize an array of SMDCs (including PDCs), also targeting less investigated tumor antigens, investigate their pharmacokinetic behavior, their implication on the immune system, as well as their tumor selectivity and antitumor activity.

HORIZON-HLTH-2022: NEXGEN-PD

DEVELOPMENT OF VACCINE FOR PARKINSON’S DISEASE

Grant: HORIZON-HLTH-2022

2023-2027

KINETO Lab Ltd. participate consortium which aim is to develop next generation vaccine platform leveraging skin immunity to provide disease-modifying treatment of Parkinson’s disease.

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Parkinson’s Disease (PD) is a major neurodegenerative disorder with no established treatment modalities capable of modifying disease pathology, and no means of early diagnosis. Vaccines targeting aSyn aggregates are a promising route to disease-modifying therapy for PD, but the current generation of PD vaccines utilise conventional formulations, which are limited in their immunogenicity and require substantial quantities of adjuvant to achieve efficacy. NEXGEN’s proprietary WISIT vaccine platform is the first of the novel class of gluconeoconjugate vaccines (GNCVs), which are administered intradermally and specifically formulated to leverage skin dendritic cells (DCs) to generate substantially stronger and more specific immune responses than conventional vaccines.

These stronger immune responses allow substantial reduction in adjuvants, while simultaneously increasing therapy efficacy. NEXGEN will identify and characterise candidate WISIT constructs targeting aSyn (PD-WISITs) and develop a novel extracellular vesicle (EV)-based biomarker assay that enables early diagnosis of PD using liquid biopsies, suitable for point of care use. Safety and efficacy of PDWISITs will be demonstrated preclinically, before being translated to first-in-human Phase I/Ib clinical trials, along with the novel EVbased biomarker assay. The results of NEXGEN will be the extraordinary accomplishments of cheap and effective disease-modifying treatment of early PD and a novel biomarker assay to diagnose and guide prodromal/early PD treatment. Further still, GNCV technology will be clinically demonstrated, which has the potential to be transformative to the treatment of a wide range of additional diseases, resulting in far-reaching impacts to the health of millions.

KRAS mutations targeting consortium

DEVELOPMENT OF DIAGNOSIS AND TARGETED THERAPY OF RASOPATHIES

Grant: NVKP-16

2016-2019

KRAS is one of the most frequently mutated oncogene in human cancer with an outstanding incidence rate among the most prevalent cancers such as colon and rectum cancer (40%), lung adenocarcinomas (30%) and pancreatic cancer (80%).

KRAS mutant human cancers are more aggressive and less sensitive to classical chemotherapeutic agents.

The aim of this project was to provide an increased understanding of the molecular mechanism of RAS-mutant induced pathologies.

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In clinical oncology the new paradigm is the introduction of the molecular targeted therapies exploiting the characteristic genetic alterations of the tumors which is frequently mutation of oncogenes. However, the efficacy of targeted therapies (i.e. anti-EGFR agents) is critically determined by the KRAS mutational status of the tumor, as mutated KRAS leads to resistance to these expensive therapies. Therefore, the mutant oncogenic KRAS in human cancer emerged as arguably the most outstanding issue in clinical oncology that should guide the future of R&D activities.

Nowadays, the successful treatment of cancer remains a great challenge. The molecular targeted therapy promise to lead to clinically useful new procedures. Within this large objective, the present project is associated with oncogenic mutations of KRAS proteins focused on cancer. However, the RAS protein and its KRAS isoform are essential players in signal transduction where some of its point mutations lead to oncogenic changes.

The project involves three universities (BME, Semmelweis University and ELTE) and two innovative companies (KINETO Lab and Fototronic) through the successful cooperation and achieved a promising results. Among these, it should be noted that we developed wild-type and mutant KRAS production and purification of protein constructs at a scale sufficient for the work planned in the project ensuring the production of protein in quantity and functionally active quality. With our protein structure studies we established the binding parameters of several candidate inhibitor molecules and characterized the binding conditions.

We designed promising ligands, the allele-specific KRAS inhibitory effect of which we began to investigate. We found that several new compounds can bind covalently to the G12C KRAS mutant through panel of assays. We have developed high-throughput binding and thiol assays, as well as KRAS functional assay. We have developed in vitro and in vivo model systems for successful toxicological and efficacy studies. With in silico docking simulations, we identified a numerous promising allele-specific inhibitor candidate for KRAS G12C, G12D G12V variants. On this for the rational examination of compounds, we developed a complex screening protocol from in vitro systems to animal models.

The reconstituted purified protein-ligand complexes were subjected to numerous biochemical, biophysical and their investigation using the enzyme kinetic method. Interaction of promising ligand molecules with KRAS mutants analyzed by multidimensional NMR studies and X-ray crystallographic studies.

HORIZON 2020 – EUROPEAN TRAINING NETWORK: MAGICBULLET

PEPTIDE-DRUG CONJUGATES FOR TARGETED DELIVERY IN TUMOR THERAPY

Grant: MAGICBULLET under the Marie Skłodowska-Curie grant agreement No 642004

2015-2018

KINETO Lab Ltd. is member of HORIZON 2020 Marie Skłodowska-Curie Actions MAGICBULLET” international research consortium built for studying the application of drug conjugates in selective tumor therapy.

The focus of the European Training Network (ETN) MAGICBULLET is on chemistry-driven approaches toward conjugates between peptides as delivery vectors that recognize tumors and anticancer drugs in order to selectively fight cancer, a topic with a high demand of research activities.

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Many tumor cells are characterized by the overexpression of certain antigens. Molecules that specifically recognize these structures are suitable as homing devices in tumor therapy. Conjugation of anticancer drugs with such a delivery vector targeting tumors would be a “magic bullet” according to the Nobel laureate Paul Ehrlich. Antibody-drug conjugates (ADC) technology have already been approved for anticancer therapy. However, ADCs have limitations with respect to tumor penetration, high manufacturing costs, and require challenging conjugation chemistry. Peptide-drug conjugates have a high drug loading capacity, easily penetrate tissue, and can be cost efficiently prepared in a homogenous form with straightforward and well-defined conjugation chemistry.

The ETN allows to develop and validate an array of new peptide-drug conjugates combining either known tumor-specific peptides or newly discovered tumor-homing peptides with potent cytotoxic drugs. The tumor-selective peptides are designed for cellular uptake mediated either by endocytosis or by cell-penetrating peptides.

The combination of an array of tumor-selective peptides targeting different receptors and different uptake mechanisms with diverse antitumor drugs acting on different cellular targets is a powerful strategy to minimize potential risks on healthy cells and increase the efficacy toward tumors. Because the number of receptors on tumor cells is limited, the combination of different target peptide–drug conjugates may enhance the bioactivity. The influence of the treatment schedule of such combination therapy on the antitumor activity will also be evaluated.

The consortium of the ETN MAGICBULLET brings together interdisciplinary expert knowledge in tumor biology, drug discovery, biochemistry, pharmacology, cell biology, organic chemistry, peptide chemistry, synthetic chemistry, medicinal chemistry, spectroscopy, conformational analysis, and computational chemistry. The training program focuses on multidisciplinary research to explore and validate molecular targets for innovative treatment or investigations on the molecular mechanisms in organ-specific metastatic growth processes. It aims at scientific multilingualism and relies on concerted learning, a combination of introductory training, hands-on learning “on the bench”, teaching by peers, and training in additional skills. This high complementarity is required for the different scientific tasks in the development pipeline.

The ETN MAGICBULLET is a tool that can:

  • identify, modify, and validate tumor-selective peptides for known and new cell surface receptor targets (e.g. integrins, Gonadotropin-releasing hormone receptors, CD13, VEGFR, cadherins);
  • study different linker systems for release of the anticancer payloads at the appropriate site;
  • conjugate known and new anticancer agents or drugs to tumor-selective peptides;
  • investigate the biological activity in vitro and in vivo to demonstrate their efficacy.

For further details regarding drug development, please contact us on info@kinetolab.hu

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