Spanish National Cancer Research Centre (CNIO) / Experimental Therapeutics

Therapeutic Approaches: Small Molecules

Therapeutic Areas of Expertise: Oncology

Center/Program Highlights: The Programme, as it stands today, is truly nested and integrated into CNIOs Basic and Translational Research Groups. The main focus of the ETP is to support drug discovery projects derived from CNIO research, or others from non-CNIO collaborators, by delivering balanced and optimised lead compounds (activity, off-target selectivity and Absorption-Distribution- Metabolism-Excretion, Toxicity (ADME-Tox) properties) with demonstrated in vivo proof-of-concept (PoC) after oral administration (mechanism of action and efficacy in tumour models).

The Programmes capabilities range from High-Throughput Screening (HTS) assay development, medicinal chemistry for hit generation, hit-to-lead and lead optimisation, to in vivo pharmacokinetics and PoC studies in animal models of human cancer. Currently, the main focus is on the discovery of novel inhibitors for kinases that, by becoming mutated or deregulated, act as key drivers in tumour development and progression; this includes the proto-oncogene serine/threonineprotein kinase Pim (PIM), dual PIM/Phosphatidylinositol 3-kinase (PI3K) inhibition, ataxia telangiectasia and Rad3 related (ATR), and microtubule associated serine/threonine kinase-like (MASTL).

In addition to full-blown drug discovery projects, ETP offers its capabilities and skills to the CNIO Research Groups, including:

HTS Platform: transfer of manually developed assays (biochemical and cellular) by CNIO researches into a high-quality HTS environment.
Chemical Library and Tool Compounds: library of 50K chemically diverse compounds with a focus on cancer targets, and a collection of FDA approved drugs for their repositioning in cancer therapy. Assistance in the identification of chemical tools and synthesis of non-available compounds.
Expertise covering in vivo pharmacokinetics, pharmacokinetics/ pharmacodynamics (PK/PD) and efficacy studies.

Major milestones achieved in 2012:

PIM: delivery of optimised leads from 2 distinct chemical series meeting Targeted Product Profile with demonstrated in vivo PoC.
Dual PIM-PI3K inhibition: a novel series of orally available dual inhibitors has been prepared; simultaneous downregulation of both pathways and strong anti-proliferative activity in the MV4:11 cell line has been demonstrated. Selected compounds demonstrated positive results in in vivo PoC studies.

The whole PIM project has been licensed to a biotech company for further development.

ATR: lead ETP-142 has demonstrated in vivo PoC in several tumour models; a novel, patentable, series of selective ATR inhibitors with oral bioavailability has been prepared.
Selected compounds from both chemical series showed to be active in in vivo animal models of cancer after oral administration. The expected deregulation of biomarkers associated with ATR inhibition was observed in PK/PD studies.

The ATR project is being object of a license, still under negotiation.

Sources of Funding: Federal/State, Industry Partnerships, Revenue


Institutional Affiliation(s):

Melchor Fernandez Almagro, 3
Madrid, 28029

Center/Program Start Date: 2006

Number of Employees: 400/23