The KINASE Platform at NMS
KINASES are one of the most relevant class of pharmaceutical targets due to their key features: a large family of enzymes with broad biological relevance and small molecule druggability.
Pioneering the early recognition of the relevance of KINASES for personalized anticancer therapy, Nerviano Medical Sciences has developed a dedicated infrastructure, the KINASES Platform, to leverage KINASE-targeted chemistry and biology approaches across multiple targets of this family.
Our KINASE Platform has already delivered potent and selective KINASE inhibitors that are registered or in clinical development.
We are committed to continue capitalizing upon our well proven knowledge and expertise in KINASES for the advancement and constant renewal of a broad portfolio of preclinical and clinical KINASE inhibitor programs in key areas of interest in Oncology and Immuno-oncology.
KINASE as drug targets
KINASES control the key intracellular pathways that are transformed in cancer, the so called “hallmarks of cancer”.
Today there are >40 drugs approved for a wide variety of solid and hematological tumors, with an impressive number of molecules in clinical development.
Despite the exponential progress of KINASE inhibitors in the last 20+ years, it is commonly recognized that the full potential of KINASE pharmacological inhibition is still to be harvested, as more knowledge is generated on the physiological and pathological role of the 500+ components of this family of enzymes.
Medical need and emerging role in combination
KINASE inhibitors are one of the best examples of the success of targeted therapy, with overcoming and durable responses in target-selected patients. However, resistance often emerges, creating the need for second and third generation drugs against the same target. Drug combinations are also being explored to fully exploit the therapeutic potential of KINASE inhibitors.
NMS KINASE Platform
An infrastructure of know how, IP and attrition reducing tools specifically developed for KINASES
It is based on integration of chemistry and biology approaches developed over 20 yrs
It facilitates the progression from target identification to clinical development of potent selective and efficacious KINASE inhibitor drugs
It generates economy of scale and secures constant delivery of new molecules with potential for first-in-class or best-in-class in different tumor settings
Constantly updated for both scientific and technological aspects
The outstanding and proven Discovery Platform is intended for a continuous renewal of our Pipeline
Target identification and validation
We are applying combined genomics and proteomics profiling of cancer cell lines and tumor samples to discover dysregulated networks and identify potential new candidate targets. Also, we are performing data mining of internal and external databases by bioinformatics approaches, including proprietary software tools developed in house, to identify new genomic alterations involving KINASES in specific tumor contexts. Large scale gene silencing and phenotypic cell screenings are routinely conducted on panels of molecularly characterized cancer cell lines, to identify syntethic lethality context and novel targets relevant in selected genetic backgrounds. Using these approaches, several novel targets have been identified at NMS and new programs with potential for first in class are on going.
KINASE Targeted Libraries (KTL)
The KINASE Targeted Library (KTL) is a proprietary collection of about 100,000 molecules designed specifically to interact with KINASES and entirely synthesized in house, distributed in >100 diverse chemical classes, broadly covering the KINASE inhibitors chemical space. The libraries are broadly tested against multiple KINASE targets over time, proving to be an optimal starting point for hit identification and initial SAR generation, as well as for the opportunistic identification of Leads against potential new targets. They are incrementally expanded over time with the support of crystallography and modeling approaches, which are also applied to improve the Hit affinity and selectivity for specific targets. The KTL, also expanded to cover other purine-binding enzymes (PTL), represent an important resource for the continuous enrichment of our compound collection endowed with extensive patent coverage and robust IP position.
KINASE Selectivity Screening (KSS)
The KINASE Selectivity Screening (KSS) consists of a panel of >100 automated biochemical KINASE assays developed over the years at NMS to evaluate the selectivity profile of compounds, and to expand the knowledge of the chemical relationship among the different KINASES, supporting the Structure Based Drug Design of our KINASE inhibitors.
The enzyme proteins used for the screening are entirely produced and characterized in house. The assay conditions allow a robust assessment (IC50s) of inhibitor potency, directly comparable across the different targets. The panel is constantly expanded overtime by the addition of novel, unexplored KINASE targets which are tested against compounds from the different KINASE projects, providing an opportunity for the discovery of new hits and leads. Over time >14,000 Lead compounds were fully profiled (IC50s) on the KSS panel.
KINASE 3D Structure
Protein X-ray crystallography in combination with modelling studies support the identification and optimization of novel therapeutic agents, from the early stages of the project up to Lead Optimization Phase. All the target proteins are produced and characterized in house and tailored to suit structural needs via an iterative construct design process. More than 35 different KINASE targets have been crystallized in complex with hundreds of proprietary compounds to support the Structure Based Drug Design process.
NMS Cell Bank consists of a panel >700 cell lines including human cancer cell lines from solid tumors and hematological malignancies, primary cells, Ba/F3 murine models dependent on driver oncogenes and reporter cell lines. All cell lines are authenticated by STR fingerprinting and most of them characterized by gene mutations, protein expression and profiled for sensitivity to compounds and siRNA libraries. Novel engineered cell lines are generated in house by trasfection, viral infection or CRISPR/CAS9, to implement unique in vitro/in vivo models for target identification and validation, compounds screening or mechanism of action studies.
These cell lines enable diverse analyses, including cell proliferation assays, large scale cellular screening, flow cytometry, imaging (high-content screening) and cellular target engagement.
A core asset of a proprietary portfolio, totaling about 1400 active patents and patent applications, extensively covers novel and potent low-molecular weight inhibitors of KINASES and other drug targets of interest.
These patents secure protection of the NMS inventions in the most important pharmaceutical markets worldwide.