Abstract 3765: Discovery and biological characterization of CX-8184, a potent inhibitor of protein kinase CK2

Autor: John K.C. Lim, William G. Rice, Adam Siddiqui-Jain, Chris Proffitt, Joshua R. Bliesath, Denis Drygin, Nanni Huser, David M. Ryckman, Diwata Macalino, Mayuko Omori, Sean O'Brien, Ryan Stansfield
Rok vydání: 2012
Předmět:
Zdroj: Cancer Research. 72:3765-3765
ISSN: 1538-7445
0008-5472
Popis: Protein kinase CK2 regulates multiple pathways that play key roles in carcinogenesis, including cell cycle progression, suppression of apoptosis, hypoxia, angiogenesis, inflammation and DNA damage repair. Overexpression of CK2 in various cancer tissues has been frequently linked to poor prognosis. All this makes targeting of CK2 highly attractive for both single agent and combination therapies. To date therapeutic targeting of CK2 proved to be challenging, with only one compound, CX-4945, entering clinical development. In phase I clinical trials CX-4945 was well tolerated, inhibited CK2 activity in PBMC, modulated the PI3K-AKT-mTOR oncogenic pathway, reduced tumor-related serum IL-6 and IL-8 biomarkers, resulted in stable disease for at least 16 weeks in 20% of treated patients, and caused single agent tumor shrinkage. Building on these successes with the first generation CK2 inhibitor, we sought to design a second generation CK2 inhibitor with distinct pharmacologic properties. The application of a focused screening cascade and iterative medicinal chemistry efforts generated CX-8184, a selective single digit nanomolar inhibitor of the CK2 enzyme that demonstrated desirable biologic properties. When evaluated against a panel of 32 cancer cell lines, CX-8184 demonstrated broad antiproliferative activity with median IC50 = 145 nM. CX-8184 suppressed NF-κB, Hif-1α and β-catenin driven transcription at concentrations of 100-300 nM, and inhibited IL-6 expression with IC50 = 30 nM. Since CK2 is known to potentiate AKT signaling, treatment of cancer cells with CX-8184 decreased phosphorylation of AKT, as well as its substrates. The Hsp90/Cdc37 machinery is regulated by CK2 and plays an important role in activation of various kinases, including members of the ErbB RTK family. CX-8184 rapidly suppressed phosphorylation of Cdc37 by CK2, leading to the deactivation of ErbB family members. In combination with erlotinib or lapatinib, CX-8184 produced synergistic killing of lung cancer and breast cancer cells, respectively. CX-8184 also inhibited the phosphorylation of XRCC1, a scaffold protein involved in DNA strand break repair that plays an important role in sensitivity of cancer cells to DNA damaging agents. Consequently, the treatment of ovarian cancer cells pre-challenged with gemcitabine and/or cisplatin with 300 nM CX-8184 led to synergistic induction of cell death. In vivo, CX-8184 demonstrated favorable PK properties with oral bioavailability and a half-life amenable to once daily dosing in mice. CX-8184 exhibited potent anti-tumor activity and was well tolerated in A431 xenograft model. The compound has also showed an acceptable pharmacological profile as evidenced by CYP, hERG and Ames testing. The pharmacokinetic and pharmacological properties and the biological activity of CX-8184, both as single agent or in combination, support its further development as a preclinical candidate.9 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3765. doi:1538-7445.AM2012-3765
Databáze: OpenAIRE
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