PUBLICATION
Design, Synthesis, and Biological Evaluation of a Novel Photocaged PI3K Inhibitor toward Precise Cancer Treatment
- Authors
- Zhang, K., Ji, M., Lin, S., Peng, S., Zhang, Z., Zhang, M., Zhang, J., Zhang, Y., Wu, D., Tian, H., Chen, X., Xu, H.
- ID
- ZDB-PUB-210421-2
- Date
- 2021
- Source
- Journal of medicinal chemistry 64(11): 7331-7340 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Cell Cycle Checkpoints/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Proliferation/radiation effects
- Dogs
- Drug Design*
- Drug Stability
- Humans
- Isoenzymes/antagonists & inhibitors
- Isoenzymes/metabolism
- Molecular Dynamics Simulation
- Neoplasms/drug therapy
- Phosphatidylinositol 3-Kinases/chemistry
- Phosphatidylinositol 3-Kinases/metabolism*
- Phosphoinositide-3 Kinase Inhibitors/chemical synthesis*
- Phosphoinositide-3 Kinase Inhibitors/metabolism
- Phosphoinositide-3 Kinase Inhibitors/pharmacology
- Phosphoinositide-3 Kinase Inhibitors/therapeutic use
- Pyrimidines/chemistry
- Pyrimidines/metabolism
- Pyrimidines/pharmacology
- Pyrimidines/therapeutic use
- Rats
- Signal Transduction/drug effects
- Ultraviolet Rays
- Xenograft Model Antitumor Assays
- Zebrafish/metabolism
- PubMed
- 33876637 Full text @ J. Med. Chem.
Citation
Zhang, K., Ji, M., Lin, S., Peng, S., Zhang, Z., Zhang, M., Zhang, J., Zhang, Y., Wu, D., Tian, H., Chen, X., Xu, H. (2021) Design, Synthesis, and Biological Evaluation of a Novel Photocaged PI3K Inhibitor toward Precise Cancer Treatment. Journal of medicinal chemistry. 64(11):7331-7340.
Abstract
Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping