CGP77675 is an Orally Active Inhibitor of Src Family Kinases
Src kinase family is a nonreceptor tyrosine kinase family. It includs 9 members: SRC, yes, Fyn and FGR, Lck, HCK, BLK, and Lyn. Specifically, Src family kinases interact with many cytoplasmic, nuclear, and membrane proteins and modify these proteins by phosphorylation of tyrosine residues. Besides, tyrosine kinase SRC is relevant to osteoclast-mediated bone resorption. Osteoporosis is a disease in which low bone mass and microstructure degradation of bone tissue lead to increased bone fragility, thus increasing the risk of fracture. Moreover, protein tyrosine kinase pp60c SRC (SRC) plays a unique and crucial role in osteoclast function. Furthermore, recent studies on osteoclast precursors have shown that SRC is involved in many osteoclast related process cytoskeleton. Therefore, specific inhibitors of Src family kinase may be useful in the treatment of related diseases. CGP77675 is an orally active and potent inhibitor of Src family kinases with anticancer activity.
CGP77675 is an orally active and potent inhibitor of Src family kinases with anticancer activity.
How does CGP77675 protect against cancer cells via Src family kinases? Let’s study it together. In the beginning, CGP77675 inhibits Src, EGFR, KDR, v-Abl, and Lck with IC50s of 0.02, 0.15, 1.0, 0.31, and 0.29 μM, respectively. CGP77675 inhibits phosphorylation of peptide substrates and autophosphorylation of purified Src (IC50s of 5-20 and 40 nM, respectively) in vitro. In addition, CGP77675 dose-dependently inhibits phosphorylation of poly-Glu-Tyr with an IC50 value of 5.5 nM, and of the optimal Src substrate (OSS) peptide with an IC50 value of 16.7 nM. These IC50 values are similar to the value obtained with chicken Src (20 nM).
Secondly, CGP77675 inhibits the parathyroid hormone-induced bone resorption in rat fetal long bone cultures with an IC50 of 0.8μM. Meanwhile, CGP77675 potently inhibits tyrosine phosphorylation of the Src substrates Fak and paxillin but has much less effect on Src (IC50 values 0.2, 0.5, and 5.7μM) in IC8.1 cells.
Thirdly, CGP77675 of 1, 5, and 25 mg/kg twice a day inhibits IL-1b-induced hypercalcemia in Mice by injecting s.c.. Nonetheless, CGP77675 partially prevents bone loss and rescues bone microarchitectural features in young ovx rats. Additionally, the parathyroid hormone-induced bone resorption in rat fetal long bone cultures was inhibited with an IC50 of 0.8 mM. All in all, CGP77675 is an orally active and potent inhibitor of Src family kinases with anticancer activity.
Missbach M, et al. Bone. 1999 May;24(5):437-49.