IC50: 3.9, 5, 26, 26, 9.2 and 11 nM for CDK4, Ark5, PDGFRβ, FGFR1, RET, and Fyn, respectively.
ON123300 is a multi-targeted kinase inhibitor.
The signaling hyperactivation of RTK is most commonly caused by EGFR mutation/amplification or PDGFR amplification/overexpression. FGFR1signaling also occurs in GBM exhibiting FGFR1 kinase domain gain-of-function mutations.
In vitro: In previous study, when Z138C and Granta 519 cells were treated with ON123300, it was found that ON123300 was efficient to inhibit the phosphorylation of Rb family proteins. Moreover, ON123300 was able to inhibit the phosphorylation of proteins that were involved in the PI3K/AKT pathway. In addition, ON123300-treated cells similarly arrested at lower concentrations, however, higher concentrations could lead to the apoptosis induction [1].
In vivo: Previous animal in vivo study showed that mouse xenograft had a strong inhibition of MCL tumor growth in ON123300-treated animals. Moreover, the treatment with ON123300 to ibrutinib-sensitive and -resistant patient-derived MCLs was able to trigger apoptosis and inhibition of both Rb and PI3K/AKT pathways, indicating that ON123300 could be an effective drug in the treatment of MCL, such as ibrutinib-resistant forms of the disease [1].
Clinical trial: Up to now, ON12300 is still in the preclinical development stage.
Reference:
[1] Divakar SK et al. Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas. Leukemia. 2016 Jan;30(1):86-93.