Abstract #4660: Discovery and characterization of CX-4945 a selective orally bioavailable small molecule inhibitor of protein kinase CK2: Phase 1 initiated

CK2 is a highly conserved, constitutively active serine/threonine protein kinase found in the cytoplasmic and nuclear compartments of multiple cell types. CK2 has been implicated in critical cellular processes such as cell cycle regulation, signal transduction, apoptosis and angiogenesis. Elevated CK2 activity has been associated with malignant transformation and aggressive tumor growth. Overexpression of CK2 has been documented in multiple cancer indications including breast tumors where CK2\#945; protein levels and CK2 activity levels are elevated 10-fold when compared to normal tissue. CK2 represents a novel target for cancer therapy. Reduction of CK2 activity using siRNA directed toward CK2\#945; caused a profound decrease in cell viability and induction of apoptosis, confirming the importance of CK2 in the regulation of cell survival. Here we present the discovery and biological characterization of CX-4945, a potent and selective inhibitor of CK2 with an IC₅₀ of 2 nM against recombinant CK2. CX-4945 was found to be remarkably selective for CK2 compared to a panel of over 100 protein kinases. CX-4945 showed a broad range of antiproliferative activity against various tumor cell lines including inflammatory breast cancer cells. CX-4945 potently inhibited endogenous CK2 activity in Jurkat cells with an IC₅₀ of 100 nM. CX-4945 induced cell line dependent G₁ or G₂ cell cycle arrest. The protein p21 plays a critical role in cell cycle regulation and has been identified as a CK2 substrate. CX-4945 showed dose and time dependent dephosphorylation of p21 at threonine 145 in multiple cell lines. CX-4945 induced apoptosis via activation of caspase 3/7. CX-4945 showed favorable pharmacokinetics and oral bioavailability in multiple species. CX-4945 demonstrated robust antitumor activity in multiple xenografts, including 70% tumor free survival, in BxPC3 xenografts. Preclinical evaluation of inhibition of human CYP450 enzymes, genotoxicity and hERG activity suggest a favorable safety profile. CK2 has emerged as an attractive anticancer target and selective inhibitors of CK2 represent a potential therapeutic strategy to target aberrant CK2 activity perpetuating many cancers. A phase 1 clinical trial of CX-4945 in patients with advanced solid tumors, Castleman\#8217;s disease or multiple myeloma has been initiated.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4660.