ABSTRACT
Human pluripotent stem cells (hPSCs) have the potential to transform medicine. However, hurdles remain to ensure safety for such cellular products. Science-based understanding of the requirements for source materials is required as are appropriate materials. Leaders in hPSC biology, clinical translation, biomanufacturing and regulatory issues were brought together to define requirements for source materials for the production of hPSC-derived therapies and to identify other key issues for the safety of cell therapy products. While the focus of this meeting was on hPSC-derived cell therapies, many of the issues are generic to all cell-based medicines. The intent of this report is to summarize the key issues discussed and record the consensus reached on each of these by the expert delegates.
Subject(s)
Cell- and Tissue-Based Therapy/standards , Patient Safety , Pluripotent Stem Cells/transplantation , Regenerative Medicine/standards , Cell- and Tissue-Based Therapy/adverse effects , Cell- and Tissue-Based Therapy/methods , Practice Guidelines as Topic , Regenerative Medicine/methods , United KingdomABSTRACT
The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57â¯617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.
Subject(s)
Amides/chemistry , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , High-Throughput Screening Assays , Humans , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Molecular Structure , Neoplasms/drug therapy , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Structure-Activity RelationshipABSTRACT
In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.
