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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Design, synthesis, and biological evaluation of novel FGFR1 PROTACs
Yu-Wei Wang1, Yu-Hui Gao1, Cheng Wang1
1Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, PR China.
Abstract:
Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound S2h, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC50 = 26.81 nM; DC50 = 39.78 nM), which incorporates an essential, nine atom-long linkers. The importance of linker length, composition, and tethering site proteolysis-targeting chimeras (PROTACs) design is emphasized, and slight modifications can significantly affect degradation potency. Meanwhile, it was verified that the degradation of FGFR1 protein at compound S2h was concentration- and time-dependent and that the protein degradation occurred through the ubiquitin-proteasome system (UPS). In summary, the newly designed heterobifunctional FGFR1 degrader, compound S2h, provides new ideas and references for the research of FGFR small-molecule degraders.
Insights
Researchers developed compound S2h, a novel proteolysis-targeting chimera (PROTAC) that effectively degrades fibroblast growth factor receptor 1 (FGFR1) in cancer cells. This discovery offers a new strategy to overcome resistance to FGFR inhibitors in cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Fibroblast growth factor receptor 1 (FGFR1) signaling dysregulation drives various cancers, including breast, prostate, and bladder cancer.
- Acquired resistance limits the long-term efficacy of current FGFR inhibitors, necessitating novel therapeutic strategies.
Purpose of the Study:
- To discover and characterize a new small molecule degrader targeting FGFR1.
- To explore the potential of proteolysis-targeting chimeras (PROTACs) in overcoming resistance to FGFR-targeted cancer therapies.
Main Methods:
- Design and synthesis of a novel heterobifunctional molecule, compound S2h, incorporating a nine-atom linker.
- Evaluation of FGFR1 degradation potency and selectivity in KG1a cells.
- Assessment of degradation kinetics (concentration- and time-dependence) and mechanism via the ubiquitin-proteasome system (UPS).
Main Results:
- Compound S2h selectively and effectively degrades FGFR1 at nanomolar concentrations (IC50 = 26.81 nM, DC50 = 39.78 nM) in KG1a cells.
- FGFR1 degradation by S2h was confirmed to be concentration- and time-dependent and mediated by the ubiquitin-proteasome system.
- The study highlights the critical role of linker characteristics in PROTAC design for potent degradation.
Conclusions:
- Compound S2h represents a promising new FGFR1 degrader with potential for cancer therapy.
- The findings provide valuable insights into the design principles of FGFR-targeted PROTACs.
- This work offers a new avenue for developing therapeutics against cancers driven by FGFR1 dysregulation.
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