SUMMARY
Replacing growth factors with a synthetic alternative molecule is an attractive opportunity to increase consistency, scalability and cost-effectiveness of cell-based products. Herein, we describe the discovery of a chemical class of FGFR1 agonists mimicking the action of basic fibroblast growth factor (bFGF), an essential component of cell-culture media. The guanylhydrazone-based molecule, TCB-32, was identified via structure-based virtual screening on the orthosteric binding site of FGFR1. It was shown to significantly increase cell proliferation by activating the FGFR1 signalling pathway like bFGF and exhibited enhanced thermostability over bFGF by containing activity over the course of several days. After extensive structure-activity relationship studies it was possible to increase potency and efficacy leading to three highly potent agonists. This finding has the potential to remove current bottlenecks in large-scale cell production as required for applications like cultivated meat or cell therapy.
GRAPHICAL ABSTRACT
Discovery of a highly potent small molecule to replace bFGF in serum-free medium
Activation of proliferation through the FGFR1-signalling pathway
Enhanced thermal stability over bFGF
SAR led to three small molecules with decreased EC50, named TCB-494, TCB-541 and TCB-621
Competing Interest Statement
H. Noori is the manager of The Cultivated B. GmbH. The authors wish to disclose pending patent application PCT/EP2024/075415 related to this work. H.N., S.L., A.S., M.B., M.F., M.Z., G.D., K.K., C.H. and F.H. are inventors on this patent. The study was funded by The Cultivated B GmbH.
