CK2A1/A2 are highly conserved, and constitutively active serine/threonine kinases. High levels of CK2A1 correlate with disease aggressiveness and is associated with poor prognosis in HNSCC, SqNSCLC, prostate cancer and AML. Deregulation of the enzymes has been shown to promote and maintain a malignant phenotype through mechanisms that affect anti-apoptotic and pro-proliferative signaling<br/>pathways. CK2 has been reported to phosphorylate and modulate the activity of several oncogenic transcription factors, including CREB, Myc, Max, Jun, Fos and Myb. In addition, CK2 inhibition or knockdown with RNAi results in growth suppression and/or apoptosis of both solid and hematologic cancer cell lines.<br/>This presentation will focus on the SAR studies leading to the discovery of a a highly potent, ATP competitive pan-CK2 inhibitor, BMS-135 with a commensurate level of cellular potency. Upon oral dosing, BMS-135 demonstrated strong PK/PD correlation and robust, anti-tumor efficacy in CK2-driven xenograft models. The presentation will also discuss further optimization to identify an orally bioavailable prodrug BMS-159 with improved pharmaceutical properties suitable for further development.

Discovery of BMS-135: An orally active imidazo[2,1-f][1,2,4]triazine pan-CK2 inhibitor for the treatment of cancer

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.