Nanaomycin A

Nanaomycin A is a selective inhibitor of DNA methyltransferase 3B (DNMT3B) with IC50 value of 500 nM [1].

In the biochemical in vitro methylation assay, Nanaomycin A showed selective inhibition of DNMT3B but not DNMT1 although it was docked to the catalytic domain of human DNMT1 in a multi-step docking approach. Nanaomycin A showed cell viability inhibition in HCT116, A549 and HL60 cells with IC50 values of 400 nM, 4100 nM and 800 nM, respectively. It decreased the genomic methylation level of these cells significantly. Besides that, Nanaomycin A treatment resulted in demethylation of the RASSF1A promoter in A549 cells. The demethylation caused by Nanaomycin A reactivated the transcription and expression of a silenced tumor suppressor gene [1].

References:
[1] Kuck D, Caulfield T, Lyko F, et al. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Molecular cancer therapeutics, 2010, 9(11): 3015-3023.

Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A.[Pubmed:21839172]

J Struct Biol. 2011 Nov;176(2):185-91.

DNA methyltransferases (DNMTs) are involved in epigenetic regulation of the genome and are promising targets for therapeutic intervention in cancer and other diseases. Until now, very limited information is available concerning the molecular dynamics of DNMTs. The natural product Nanaomycin A is the first selective inhibitor of DNMT3B that induce genomic demethylation. Herein we report long (>100ns) molecular dynamics simulations for human DNMT3B bound to Nanaomycin A with and without the presence of the cofactor S-adenosyl-L-methionine (SAM). We concluded that SAM favors the binding of Nanaomycin A to DNMT3B. Key interactions of Nanaomycin A with DNMT3B involve long lasting interactions with Arg731, Arg733, Arg832, and the catalytic Cys651. Results further support the previous hypothesis that Nanaomycin A has key interactions with amino acid residues involved in the mechanism of methylation. This work represents one of the first molecular dynamics studies of DNMT3B. Results of this work shed light on the structure and binding recognition process of a key epigenetic enzyme with a small molecule inhibitor.

Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells.[Pubmed:20833755]

Mol Cancer Ther. 2010 Nov;9(11):3015-23.

Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present Nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, Nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes.

New compounds, nanaomycin F and G, discovered by physicochemical screening from a culture broth of Streptomyces rosa subsp. notoensis OS-3966.[Pubmed:26100318]

J Biosci Bioeng. 2015 Nov;120(5):596-600.

Two new compounds, nanaomycin F and G, were isolated by physicochemical screening method from cultured broth of Streptomyces rosa subsp. notoensis OS-3966, which is known to produce Nanaomycin A, B, C, D, and E. Nanaomycin F is a new Nanaomycin Analog, a 4a-hydroxyl analog of nanaomycin B. Nanaomycin G has a unique skeleton with 1-indanone infused with a tetrahydropyran ring. Nanaomycin A possesses broad antimicrobial activity but nanaomycin F and G demonstrated no bioactivity against all bacteria and fungi tested in this study. In addition, in both nanaomycin F and G, the production of superoxide radicals was majorly decreased in comparison to Nanaomycin A. It was considered that the antimicrobial properties were lost as a result of the decrease in production of the superoxide radicals.

Nanaomycin H: A new nanaomycin analog.[Pubmed:28202308]

J Biosci Bioeng. 2017 Jun;123(6):765-770.

Physicochemical screening identified a new Nanaomycin Analog, nanaomycin H, which was isolated from a culture broth of Streptomyces rosa subsp. notoensis OS-3966. This microorganism is already known to produce seven nanaomycin compounds, (Nanaomycin A to G). Structural elucidation of nanaomycin H showed it to be a pyranonaphthoquinone with a mycothiol moiety. A N-acetylcysteine S-conjugate of nanaomycin H, without alpha-glucosamine linked to myo-inositol moiety, mercapturic acid derivative, was also detected in the same culture broth. Mercapturic acid derivatives of secondary metabolites are known to be produced for xenobiotic metabolism outside microbial cells. Mycothiol acts as a detoxifier to help prevent cell damage from factors such as oxidative stress. The production of O2(-) generated by reduction of Nanaomycin A is correlated with antibacterial activity. Mycothiol-containing nanaomycin H proved to be markedly decreased in O2(-) and did not express any notable antimicrobial activity. It is suggested that nanaomycin H is produced in the detoxification process.

Nanaomycin A is the first selective DNMT3B inhibitor with an IC50 of 500 nM. Nanaomycin A, a quinone antibiotics, reactivates silenced tumor suppressor genes in human cancer cells. Nanaomycin A inhibits in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM.

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