CK2 is a small family of serine/ threonine kinases (CK2A1, CK2A2) with nearly identical sequence differing only in C-terminus. Phosphorylation of its substrates occurs by utilizing either ATP or GTP as a phosphate donor. CK2 is reported to phosphorylate and modulate the activity of several oncogenic transcription factors, including CREB, Myc, Max, Jun, Fos and Myb. Aggressiveness of several cancer types such as HNSCC, SqNSCLC, prostate cancer and AML correlates with higher levels of CK2A1 and is associated with poor prognosis. Also, dysregulation of the enzymes has been shown to promote and maintain a malignant phenotype through mechanisms that affect anti-apoptotic and pro-proliferative signaling pathways. Further, CK2 inhibition or knockdown with RNAi results in growth suppression and/or apoptosis of both solid and hematologic cancer cell lines. This presentation will focus on the SAR studies leading to the discovery of a highly potent, ATPcompetitive pan-CK2 inhibitor, BMS-699 with a commensurate level of cellular potency. Upon oral dosing, BMS-699 demonstrated durable PK/PD response and robust, anti-tumor efficacy in CK2-driven models. The presentation will also discuss further optimization to identify an orally bioavailable self-immolative prodrug, BMS-211 with improved pharmaceutical properties for future development

Discovery of BMS-211, a self-immolative prodrug as an orally active imidazo[2,1-f][1,2,4]triazinepan-CK2 inhibitor for the treatment of cancer

2019 Fall National Meeting

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