生物活性

• 靶点	Casein Kinase 2α IC50:1nM

• 描述Protein kinase CK2 is a tetrameric enzyme with two catalytic subunits and two regulatory subunits that constitutively actives serine/threonine protein kinase as a prototypical non-oncogene. CX-4945 is a selective inhibitor of CK2 catalytic subunits with an IC50 value of 1 nmol/l. Four-hour exposure to 5 and 10 μmol/l CX-4945 in BT-474 cells and BxPC-3 cells caused rapid dephosphorylation of CK2 phophorylation site, Akt (S129), and both canonical regulatory sites, Akt (T308) and Akt (S473). Treatment of BT-474 cells with 1 - 10 μmol/l CX-4945 for 24 hours induced a G2/M cell-cycle arrest, while the treatment of BxPC-3 cells led to G1/M arrest. Incubating HUVEC cells with 0.1 – 10 μmol/l CX-4945 led to rapid dephosphorylation of Akt (S129), Akt (T308) and Akt (S473) at 4 hours. Also in HUVEC cells, reduced phosphorylation at the CK2-phosphorylation sites on PTEN (S370/S380) was also observed after 24-hour exposure to 0.1 – 10 μmol/l CX-4945. CX-4945 inhibited HUVEC cell proliferation, migration, and tube formation with IC50 values of 5.5, 2, and 4 μmol/l at 72 hours, 24 hours and 18 hours, respectively. Treatment of BT-474 and BxPC-3 cells under hypoxic conditions with 5 μmol/l CX-4945 for 48 hours prevented the downregulation of p53 and pVHL. The activation of HIF-1α transcription in Hela cells under hypoxic versus normoxic conditions was also suppressed by 12.5 and 25 μmol/l CX-4945 48 hours after the treatment. In BT-474 xenograft mice, oral administration of 25 and 75 mg/kg CX-4945 twice a day for 31 days inhibited 88% and 97% tumor growth, respectively. In BxPC-3 mouse model, 75 mg/kg bid oral gavage of CX-4945 for 35 days resulted in 93% tumor growth inhibition.
• 作用机制CX-4945 acts as an ATP-competitive inhibitor of both isoforms of CK2 catalytic subunits, CK2α and CK2α’, directly blocking the phosphorylation of Akt at Serine 129 in PI3K/Akt signaling pathway.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A431	10 μM	Function Assay	30 min	attenuates PI3K-Akt-mTOR signaling	22387988
  A431	10 μM	Function Assay	4-24 h	enhances apoptosis with erlotinib	22387988
  A549	3/10 μM	Function Assay	48 h	suppresses the micropillar-induced expression of p-FAK	26318800

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• 动物研究
  剂量	Mice: 25 mg/kg - 75 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Dose 5 mg/kg (i.v.) 25 mg/kg (p.o.) 5.2 mg/kg (i.v.) 10.5 mg/kg (p.o.) 1.9 mg/kg (i.v.) 8.2 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 20% (p.o.) 48% (p.o.) 51% (p.o.) T1/2 5 h (i.v.) 11.6 h (i.v.) 8.3 h (i.v.) AUC 2009 ng·h/ml (p.o.) 42343 ng·h/ml (p.o.) 5646 ng·h/ml (p.o.) CL 2.5 L/h/kg (i.v.) 0.1 L/h/kg (i.v.) 0.7 L/h/kg (i.v.) Cmax 311 ng/ml (p.o.) 7369 ng/ml (p.o.) 2178 ng/ml (p.o.) Vss 18.1 L/kg (i.v.) 2.0 L/kg (i.v.) 8.9 L/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00891280	Advanced Solid Tumors ... more >> Breast Cancer Inflammatory Breast Cancer Castleman's Disease Multiple Myeloma Collapse <<	Phase 1	Unknown	December 2011	United States, Arizona ... more >> Mayo Clinic Arizona Recruiting Scottsdale, Arizona, United States, 85259 Contact: Clinical Trials Office Mayo Clinic Cancer Center    507-538-7623       Principal Investigator: Donald Northfelt, MD          United States, Colorado Front Range Cancer Specialists Recruiting Fort Collins, Colorado, United States, 80528 Contact: P. Zeller    970-212-7609       Principal Investigator: Robert F Marschke, MD          Front Range Cancer Specialists Recruiting Loveland, Colorado, United States, 80528 Contact: Pat Zeller    970-212-7609       Principal Investigator: R. McFarland, MD          United States, Texas U T M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: R. Alvarez, MD       ralvarez@mdanderson.org    Principal Investigator: R. Alvarez, MD Collapse <<
  NCT03571438	Kidney Cancer	Not Applicable	Recruiting	September 30, 2024	France ... more >> Grenoble Alps Hospital Recruiting Grenoble, France, 38043 Contact: Jean-Luc Descotes, PU-PH Collapse <<
  NCT02128282	Cholangiocarcinoma	Phase 1 Phase 2	Recruiting	November 2021	United States, Arizona ... more >> Mayo Clinic Recruiting Scottsdale, Arizona, United States, 85259-5499 Contact: Mayo Clinic Clinical Trials Office    855-776-0015       Principal Investigator: Mitesh Borad, M.D.          United States, Colorado University of Colorado- Denver Recruiting Aurora, Colorado, United States, 80045 Contact: Amy Szilard    720-848-0702    Amy.Szilard@ucdenver.edu    Principal Investigator: Sarah (Lindsey) Davis, MD          United States, Florida Mayo Clinic Recruiting Jacksonville, Florida, United States, 32224 Contact: Mayo Clinic Clinical Trials Office    855-776-0015       Principal Investigator: Kabir Mody, MD          United States, Minnesota Mayo Clinic Recruiting Rochester, Minnesota, United States, 55905 Contact: Mayo Clinic Clinical Trials Office    855-776-0015       Principal Investigator: Joleen Hubbard, MD          United States, Texas Texas Oncology - Baylor Charles A. Sammons Cancer Center Recruiting Dallas, Texas, United States, 75246 Contact: Tammy Carmical, RN    214-370-1937    tammy.carmical@usoncology.com    Principal Investigator: Carlos Becerra, M.D.          Texas Oncology-Tyler Recruiting Tyler, Texas, United States, 75702 Contact: Karen Poe, RN    903-579-9869    karen.poe@usoncology.com    Principal Investigator: Donald A Richards, M.D.          Korea, Republic of Asan Medical Center Recruiting Seoul, Songpa-gu, Korea, Republic of, 138-736 Contact: Heung-Moon Chang, MD    82-3010-3219 ext 3210    changhm@amc.seoul.kr    Contact: Seok kyung Jeong    82-2-3010-5634    jsk0213@amc.seoul.kr    Samsung Medical Center Recruiting Seoul, Korea, Republic of Contact: Eunyou Lee    82-2-3410-0955    ley0709@samsung.com    Principal Investigator: Joon Oh Park, MD          Seoul National University Hospital Recruiting Seoul, Korea, Republic of Contact: Myoungsun Choi    82-2-2072-7612    iamyou3@hanmail.net    Principal Investigator: Do-Youn Oh, MD          Severance Hospital, Yonsei University Health System Recruiting Seoul, Korea, Republic of Contact: So Young Hwang    82-2-2228-8180    syhwang@yuhs.ac    Principal Investigator: Sun Young Rha, MD          Taiwan China Medical University Hospital Recruiting Taichung City, Taiwan Contact: Pei-Chen Hsu    +886-4-2205-2121    peggyshiu0807@gmail.com    Principal Investigator: Li-Yuan Bai, M.D. Collapse <<

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• 参考文献

• [1] Siddiqui-Jain A, Drygin D, 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):10288-98.

  [2] Pierre F, Chua PC, 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 Jan 27;54(2):635-54.