RGNCY-0056 (ON123300 Multikinase inhibitor)

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ON123300 is a low molecular weight multikinase inhibitor that was identified by screening for a new brain tumor chemotherapy.  ON123300 is a strong inhibitor of Ark5 and CDK4 and growth factor receptor tyrosine kinases such as PDGFRb.   In U87 glioma cells, ON123300 inhibited proliferation (IC50 = 3.4 + 0.1 mmol/L).  It reduced phosphorylation of Akt but induced Erk activation due to relieving Akt-mediated CRaf S259 inactivation and activating a p70S6K-initiated PI3K-negative feedback- loop.  ON123300 demonstrated  favorable pharmacokinetic profile for development as a brain tumor therapy.  Another study demonstrated the dual inhibition of CDK4/Rb and PI3K/AKT/mTOR by ON123300 resulted in the lethality of mantle cell lymphomas in mouse xenograft models.  Furthermore, treatment of multiple myeloma cell lines and primary cells with ON123300 resulted in rapid cell cycle arrest and apoptosis.  It was also effective in inhibiting tumor growth in mouse multiple myeloma xenograft models.  ON123300 has shown potent anti-cancer activity in a variety of tumor models and has potential for development as a new cancer therapy.

Systematic Name:  8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

SMILES: O=C1N(C2CCCC2)C3=NC(NC4=CC=C(N5CCN(C)CC5)C=C4)=NC=C3C=C1C#N

Formula: C24H27N7O

Mol Wt: 429.53

PMID:  23180160