Monday, April 27, 2015

Drugs in Clinical Pipeline: CX-4945

CX-4945 [5-((3-chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid] is an orally bioavailable ATP-competitive inhibitor of protein kinase Casein kinase 2 (CK2) in clinical trials for cancer. Protein kinase CK2 is a constitutively active serine/threonine kinase with a long history as a pro-survival, anti-apoptotic kinase. Given the wide spread overexpression of CK2 in multiple cancers and its role in multiple non-oncogenic processes required to sustain the cancer phenotype, a selective inhibitor of CK2 is an attractive targeted approach to treating cancer.

The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of the  mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling in multiple pathways [1].

CX-4945 is currently under evaluation as an orally administered single agent in a Phase I clinical trial in patients with solid tumors (including breast, prostate, pancreatic cancers and inflammatory breast cancer, as well as multiple myeloma and Castleman's Disease). During this trial, CX-4945 has established favorable pharmacokinetic, pharmacodynamic and safety profiles. Measurement of mechanism and tumor-related biomarkers in patients reveal that CX-4945 hits the CK2 target and down-modulates the PI3K/Akt pathway. The pharmacokinetic and biomarker data demonstrate that CX-4945 is achieving pharmacologically active levels in plasma and in tumor cells and elicits a clear pharmacodynamic response in humans. Together, the findings establish CX-4945 as a promising therapeutic agent for targeting multiple cancers.

Cylene Pharmaceuticals Inc/Senhwa Biosciences, Inc is developing CX-4945.

The activity of CX-4945 is as follows:

IC50 (CK2α) = 1 nM
IC50 (CK2α’) = 1 nM
Ki  (CK2 holoenzyme) = 0.38 nM

Common Name: CX-4945
Synonyms:  CX-4945, CX4945; CX 4945; Silmitasertib
IUPAC Name: 5-((3-chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid
CAS Number: 1009820-21-6
Mechanism of Action: Kinase Inhibitor; CK2 Inhibitor
Indication: Various Cancers; AML
Development Stage: Phase I/II
Company: Cylene Pharmaceuticals Inc/Senhwa Biosciences, Inc

CX-4945 was screened at 0.5 µM against a panel of 238 kinases (Millipore) to assess its selectivity profile. At 0.5 µM, CX-4945 showed no major inhibition of the vast majority of tested kinases, including all isoforms of PI3K, Akt, PDK1, and mTOR. IC50 values were measured against the seven kinases [DAPK3, FLT3, TBK1, CLK3, HIPK3, PIM1, CDK1/cyclinB] for which it exhibited greater than 90% inhibition at 0.5 µM. As anticipated, CX-4945 displayed an excellent selectivity profile, which is even more remarkable when considering the low molecular weight (349.8 g/mol) of the molecule. In addition, CX-4945  was evaluated at a concentration of 10 µM in relevant cell-based assays for FLT3, PIM1, and CDK1 and was found to be functionally inactive against these kinases [2].

CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer [3].

Elevated Casein kinase 2 (CK2) activity has been associated with malignant transformation and aggressive tumor growth and overexpression of CK2 has been documented in multiple types of cancer. CK2 has emerged as a potential anticancer target and inhibition of CK2 represents a potential therapeutic strategy to target a specific molecular defect perpetuating many cancers. CX-4945 has demonstrated potent inhibition of CK2 enzymatic activity. A phase I study will evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) effects of CX-4945 administered to patients with malignancies or lymphoproliferative disorders known to overexpress CK2 including advanced solid tumors, Multiple Myeloma and Castleman's Disease [4].

1. Siddiqui-Jain, A.; et. al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 2010, 70(24), 10288-10298.
2. Pierre, F.; et. al. Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J Med Chem 2011, 54(2), 635-654.
3. Pierre, F.; et. al. Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer. Mol Cell Biochem 2011, 356(1-2), 37-43.
4. Dose-escalation Study of Oral CX-4945. NCT00891280 (retrieved 27-04-2015)
5. Study of CX-4945 in Combination With Gemcitabine and Cisplatin for Frontline Treatment of Cholangiocarcinoma. NCT02128282 (retrieved 27-04-2015)