Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Apr 7;11(5):713-719.
doi: 10.1021/acsmedchemlett.9b00561. eCollection 2020 May 14.

New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes

Loganathan Rangasamy  1 , Irene Ortín  1 , José María Zapico  1 , Claire Coderch  1 , Ana Ramos  1 , Beatriz de Pascual-Teresa  1
Affiliations

New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes

Loganathan Rangasamy et al. ACS Med Chem Lett. .

Abstract

Four potent CK2 inhibitors derived from CX-4945 are described. They also provided nanomolar activity against HDAC1, therefore having promising utility as dual-target agents for cancer. The linker length between the hydroxamic acid and the CX-4945 scaffold plays an important role in dictating balanced activity against the targeted enzymes. The seven-carbon linker (compound 15c) was optimal for inhibition of both CK2 and HDAC1. Remarkably, 15c showed 3.0 and 3.5 times higher inhibitory activity than the reference compounds CX-4945 (against CK2) and SAHA (against HDAC1), respectively. Compound 15c exhibited micromolar activity in cell-based cytotoxic assays against multiple cell lines.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
HDACi based dual inhibitors in clinical trials.
Figure 2
Figure 2
Design strategy for dual CK2/HDAC1 inhibitors.
Figure 3
Figure 3
PyMOL stick and cartoon representation of the best docking pose of compound 15c to CK2. For the sake of clarity, only polar hydrogens are shown, and hydrogen bonds have been highlighted with dashed lines.
Figure 4
Figure 4
PyMOL stick and cartoon representation of the best docking pose of compound 15c to HDAC1. For the sake of clarity, only polar hydrogens are shown, and hydrogen bonds have been highlighted with dashed lines.
Scheme 1
Scheme 1. Convergent Strategy for Dual Inhibitor Synthesis
Scheme 2
Scheme 2. Synthesis of Compound 8
Reagents and conditions: (a) MeOH, H2SO4, reflux, 12 h; (b) KOAc, Pd(dppf)Cl2, bis(pinacolate)diboron, DCM, dioxane, 80 °C, overnight; (c) H2, Pd/C 10%, EtOAc, RT, 12 h; (d) MeOH, H2SO4, reflux, 12 h; (e) NaOAc, Pd(dppf)Cl2 DCM, dioxane, 125 °C, 12 h; (f) neat POCl3, reflux, 2 h.
Scheme 3
Scheme 3. Synthesis of Ω-Amine (Benzyloxy)amino Compounds 12a–d as HDAC1 Scaffold
Reagents and conditions: (a) NaN3, DMF, 77 °C, 48 h; (b) HCl·H2N-OBn, HBTU, DIPEA, DMF, RT, 12 h; (c) H2, Pd/C, EtOAc, RT, 2 h.
Scheme 4
Scheme 4. Synthesis of Dual Inhibitors 15a–d Isolated as TFA Salts
Reagents and conditions: (a) DMF, K2CO3; 135 °C, 55 min, MW irradiation; (b) for 14a–c: H2, Pd/C 10%, MeOH, 4 bar, RT, 12 h; for 14d: H2 atmosphere and MeOH:THF 1:1 as solvent, 12 h; (c) LiOH, RT, 96 h.
See this image and copyright information in PMC

References

    1. Wu S.; Zhu W.; Thompson P.; Hannun Y. A. Evaluating intrinsic and non-intrinsic cancer risk factors. Nat. Commun. 2018, 9 (1), 3490. 10.1038/s41467-018-05467-z. - DOI - PMC - PubMed
    1. Lopez J. S.; Banerji U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat. Rev. Clin. Oncol. 2017, 14 (1), 57–66. 10.1038/nrclinonc.2016.96. - DOI - PMC - PubMed
    1. Zhou J.; Jiang X.; He S.; Jiang H.; Feng F.; Liu W.; Qu W.; Sun H. Rational design of multitarget-directed ligands: strategies and emerging paradigms. J. Med. Chem. 2019, 62 (20), 8881–8914. 10.1021/acs.jmedchem.9b00017. - DOI - PubMed
    1. Stazi G.; Fioravanti R.; Mai A.; Mattevi A.; Valente S. Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer. Curr. Opin. Chem. Biol. 2019, 50, 89–100. 10.1016/j.cbpa.2019.03.002. - DOI - PubMed
    1. Luan Y.; Li J.; Bernatchez J. A.; Li R. Kinase and histone deacetylase hybrid inhibitors for cancer therapy. J. Med. Chem. 2019, 62 (7), 3171–3183. 10.1021/acs.jmedchem.8b00189. - DOI - PubMed

LinkOut - more resources