Projects

IOCB Tech’s main responsibilities include identifying commercially attractive projects developed within the IOCB, followed by analyzing their market potential and patentability, protecting their intellectual property, supporting the given projects’ development in the form of project management, finding commercial partners, and negotiating the contractual terms for signing license agreements.

We have participated in the negotiating and concluding of more than a dozen key license agreements with important pharmaceutical partners including Gilead Sciences, Merck, Novo Nordisk, and SHINE Technologies.

Our main areas of interest are the development of new drugs, diagnostics, and research tools. Our current portfolio includes projects focusing on a variety of therapeutic areas: e.g., the central nervous system, inflammation, cancer, and microbial resistance, as well as separation methods and research tools.

Inhibiting purine nucleoside phosphorylase to treat T-cell malignancies – a viable approach or not? Active

Scientists:
Principal Investigator: Zlatko Janeba (IOCB Prague). PNP Team (IOCB Prague): Jan Skácel, Michal Česnek, Pavel Kraina, Helena Mertlíková-Kaiserová, Jaroslav Kozák, Pavlína Maloy Řezáčová

Challenge

T-cell leukemias/lymphomas are a clinically heterogenous group of rare, but often aggressive malignancies. Current treatment options for T-cell leukemias/lymphomas are limited, especially for patients who have relapsed after the first-line treatment. The median overall survival for relapsed peripheral T-cell lymphoma has been estimated at ca. 6 months (Mak 2013; DOI: 10.1200/JCO.2012.44.7524).

Purine nucleoside phosphorylase (PNP) is a ubiquitous enzyme required for purine metabolism. T-cell proliferation is known to be crucially dependent on the PNP activity. Thus, effective PNP inhibition could be beneficial in conditions characterized by malignant T-cell growth. The first (and so far only) marketed PNP inhibitor, forodesine, is currently available only in Japan (as of Jan 2021, brand name Mundesine).

Beside T-cell malignancies, PNP has been proposed as a potential therapeutic target for the treatment of bacterial and parasitic infections (Mycobacterium tuberculosis, Plasmodium falciparum).

Technology

We have designed novel potent inhibitors of the human and bacterial (Mycobacterium tuberculosis) PNP enzyme. Our most potent inhibitors exhibit IC₅₀ values in low nanomolar range for both enzyme subtypes. Cytotoxicity toward various T-lymphoblastic cell lines with CC₅₀ values as low as 9 nM was also observed. The cytotoxic effect was highly selective; other (non-T) cancer cell lines (HeLa S3, HL60, HepG2) and primary peripheral blood mononuclear cells (PBMCs) were unaffected by the treatment (up to 10 μM). The results are further supported by an extensive crystallography study of eight enzyme-inhibitor complexes, elucidating structure activity relationship. Current generation of inhibitors significantly improves ADME properties and activities of the compounds. The ultimate goal is to develop non-ionizable and permeable PNP inhibitors that would enable PNP targeted therapy.

Commercial opportunity

This project is offered for co-development or licensing.

Development status

Lead optimisation

Keywords

purine nucleoside phosphorylase (PNP) T-cell leukemia T-cell lymphoma