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ISOTOPIC LABELING FOR DRUG INNOVATION

Periodic Reporting for period 2 - ISOTOPICS (ISOTOPIC LABELING FOR DRUG INNOVATION)

Reporting period: 2018-01-01 to 2019-12-31

Presently, less than one drugable compound on ten entering clinical trials effectively reaches the market. This excessive drug attrition rate is mainly due to insufficient preclinical studies of new chemical entities. Drug Design and Development (DDD) might be derisked by the use of isotopic (radio)labeling which enables to tag and trace drug candidates in vivo at an early stage of drug research. However, this task is often difficult and time-consuming due to the scarcity of efficacious late-stage labeling methods and the lack of specialized chemists, familiar with isotopic chemistry but also medicinal chemistry applied in both the academic and industrial sectors.
The ISOTOPICS Innovative Training Network, gathering 5 academics and 3 industrial beneficiaries, has therefore defined 3 main objectives:
i) To train 15 Early Stage Researchers (ESRs) as the next generation of European chemists with expertise in isotopic labeling and advanced medicinal chemistry through a first-class research training program combined with a highly interactive secondments plan;
ii) To develop innovative and general isotopic labeling chemistry and radiochemistry to streamline the synthesis of labeled small-molecule drugs and biologics for therapy but also for diagnosis. The project is limited to hydrogen isotopes (2H, 3H), carbon radio-isotopes (11C, 14C) and fluorine radio-isotope (18F) which are well-admitted for such preclinical/clinical studies by the drug regulation agencies.
iii) To work closely with the European pharmaceutical industry to apply the new labeling methods to drugs currently in development.
Main Goals of ISOTOPICS Network:
High quality science
High quality training
Joint papers
Leverage other grant application
Decrease drug attrition and streamline DDD
Key achievements:
15 Fellows appointed (ESR)
Gender balance (> 53% women)
-5 training schools completed according to the training plan.
7 ISOTOPICS International Meetings
Completion of secondments (typically 2/ESR including 1 in industry)
Awarded: 4 prizes for oral communication (Award for junior synthesis), and 2 prizes for posters, 1 fellow PIs recipient of an ERC-Advanced and 1 FET Open granted in 2019
30 scientific papers published in high impact factor journals (regarding speciality), global mean impact factor = 11.51.
The collaborative training and research program of ISOTOPICS is outlined in six work packages (WP). During the last 2 years of the project, the implementation of each WP was achieved as follows:
WP1: COORDINATION AND PROJECT MANAGEMENT
Three ISOTOPICS meetings, attended by Principal Investigators (PIs), ESRs and the Advisory Board Members, were organized during the second reporting period. These meetings gave the opportunity to the ESRs to present their research results and communication actions to all the PIs and to discuss about the implementation of the ISOTOPICS project. The progresses of the PhD projects and the different dissemination and communication actions realised by the ESRs confirmed the fruitful research work of the consortium. This was also the opportunity to attend plenary lectures given by prominent external scientists.
WP2: INNOVATIVE ISOTOPIC LABELING CHEMISTRY
Hydrogen Isotope Exchange methodology was developed through a collaboration between 3 beneficiaries (CEA, CNRS SAN) using various catalyst (nanoparticles, soluble metal complexes). Nine papers were published during RP2 demonstrating the great potential for this method for the deuteration and tritiation of drugs and drugable compounds. Three papers related to catalysts and its applications in isotopic labelling were published too. Several methodologies were developed for the implementation of late stage labeling of compounds using carbon isotopes. Nine papers were published in total, all related to studies concerning late stage carbon isotope labeling, a simplified method for 11C labeling using flow chemistry, late stage carbon isotope exchange using labelled CO2, visible light methods and new trends applications. Regarding 18F labeling, new efficient methodologies were developed in particular for the stereocontrolled introduction of fluorine and di and trifluoromethylation of unactivated carbon centers. In total eight papers were published, demonstrating the great value and efficiency of the various collaboration (ULG/UCB/ UOXF).
WP3: APPLICATION FOR THE ISOTOPIC LABELING OF DRUGS AND BIOLOGICS
Innovative methods for the isotopic labeling of drugs were applied on model drugs or drugable compounds for hydrogen isotopes exchange and carbon isotopes exchange. The 18F labeling methodologies, developed by ULG and UCB, are being applied to the synthesis of a potential PET tracer. CEAk and AZ have developed an 18F labeling methodology of a potential radiotracer for non-small cell lung carcinoma. In vivo testing of labelled molecules are underway.
WP4: TRAINING
During RP2, 2 trainings have been organised for our ESRs. During the 4th session, the ESRs acquired basic knowledge in non-isotopic labeling and imaging. They also participated in several workshops about radiochemistry automation, cyclotron targetery, clinical PET imaging or management principles and career. The 5th session included general courses about labeling chemistry, cancer imaging and clinical trials but also proposal writing and scientific project set-up and management workshops. The ESRs have also visited laboratories in beneficiary premises and enjoyed nice social events with the organizing teams. Many ESRs have done secondments as scheduled in Partners’ institutions in order to get an experience in a distinct sector.
WP5: DISSEMINATION AND COMMUNICATION
The ISOTOPICS website was regularly updated to inform about the goals, the ESRs profiles, the events and achievements of the project. The 2nd and 3rd ISOTOPICS Newsletter edited in 2018 and 2019, are available from the website. The last one will be published in February 2020. The ISOTOPICS ESRs attended over 60 scientific national and international symposia and workshops to present their research results through posters (27) or oral communications (33). PIs and ESRS participated to open science events. The Coordinator published an article in an Open Access governmental journal and presented a poster about the project in an International symposium in June 2018.
ISOTOPICS has initiated and/or reinforced partnerships between European academic and non-academic researchers in the isotopic labeling chemistry environment. It will foster the development and enhance productivity of the European research in this scientific field. As described in the ISOTOPICS scientific work packages (WP2 and WP3), a particular effort is made to design late-stage straightforward and efficacious isotopic labeling methods with a particular interest in labeling fragile biomolecules. The 15 ISOTOPICS ESRs benefited from a first-class training program and gained valuable experience on research and innovation in isotopic chemistry. It should therefore have great impact on their future careers. Eight ESRs found positions (6 non-permanent and 2 permanent) at the end of their ISOTOPICS contract. At the end of February 2020, Seven ESRs have defended their thesis and have been awarded with the doctoral degree. Other defenses are planed for 2020. The ISOTOPICS project is expected, in fine, to boost innovation and development of the European academic research and pharmaceutical Industry.