ChemInform Abstract: Enediynes: Exploration of Microbial Genomics to Discover New Anticancer Drug Leads

Shen, Ben; Hindra, Hindra; Yan, Xiaohui; Huang, Tingting; Ge, Hui‐Ming; Yang, Dong; Teng, Qihui; Rudolf, Jeffrey D.; Lohman, Jeremy R.

doi:10.1002/chin.201506306

Cited by 12 publications

(19 citation statements)

References 1 publication

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“…56−58 Comparison of known enediyne BGCs revealed that only a set of five genes is conserved in all clusters, encoding the enediyne PKS, a thioesterase, and three unknown proteins commonly referred to as SgcE, SgcE10, and SgcE3/E4/E5, respectively, based on the C-1027 BGC nomenclature. 57,58 Cluster 13 contains the minimal enediyne PKS cassette as MicB006_4939 (SgcE), MicB006_4940 to MicB006_4942 (SgcE3/E4/E5), and MicB006_4938 (SgcE10) (Table S2).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Complete Genome of Micromonospora sp. Strain B006 Reveals Biosynthetic Potential of a Lake Michigan Actinomycete

et al. 2018

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Actinomycete bacteria isolated from freshwater environments are an unexplored source of natural products. Here we report the complete genome of the Great Lakes-derived Micromonospora sp. strain B006, revealing its potential for natural product biosynthesis. The 7-megabase pair chromosome of strain B006 was sequenced using Illumina and Oxford Nanopore technologies followed by Sanger sequencing to close remaining gaps. All identified biosynthetic gene clusters (BGCs) were manually curated. Five known BGCs were identified encoding desferrioxamine, alkyl- O-dihydrogeranylmethoxyhydroquinone, a spore pigment, sioxanthin, and diazepinomicin, which is currently in phase II clinical trials to treat Phelan-McDermid syndrome and co-morbid epilepsy. We report here that strain B006 is indeed a producer of diazepinomicin and at yields higher than previously reported. Moreover, 11 of the 16 identified BGCs are orphan, eight of which were transcriptionally active under the culture condition tested. Orphan BGCs include an enediyne polyketide synthase and an uncharacteristically large, 36-module polyketide synthase-nonribosomal peptide synthetase BGC. We developed a genetics system for Micromonospora sp. B006 that will contribute to deorphaning BGCs in the future. This study is one of the few attempts to report the biosynthetic capacity of a freshwater-derived actinomycete and highlights this resource as a potential reservoir for new natural products.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Complete Genome of Micromonospora sp. Strain B006 Reveals Biosynthetic Potential of a Lake Michigan Actinomycete

et al. 2018

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“…24 The bacterial strains were cultured overnight and diluted to 10 6 CFU/mL in Luria−Bertani (LB) broth. YPMs were dissolved in DMSO and serially diluted to 20 different concentrations (1,2,4,8,16,32,64,128,256, and 512 ng/mL; 1, 2, 4, 8, 16, 32, 64, 128, 256, and 512 pg/mL) using LB broth on a 96well plate. Vancomycin was dissolved in DMSO and serially diluted to 10 concentrations (0.03125−16 μg/mL) using LB broth on each 96well plate.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…[6][7] Enediynes are the most cytotoxic small molecules known to date, and are very promising payloads in ADCs. 8 Calicheamicin, a 10-membered enediyne natural product, is used as the payload for Mylotarg and Besponsa for the treatment of acute myeloid leukemia or acute lymphoblastic leukemia, respectively. Another ADC consisting of an anthraquinone-fused enediyne, uncialamycin and an anti-mesothelin mAb, showed sub-nanomolar potency against mesothelin-positive lung cancer cell lines in vitro (IC 50 = 0.88 nM, H226 cell line).…”

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Yangpumicins F and G, Enediyne Congeners from Micromonospora yangpuensis DSM 45577

et al. 2019

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Enediyne natural products are among the most cytotoxic small molecules and thus excellent payload candidates for the development of antibody-drug conjugates (ADCs). Here we report the isolation and structural elucidation of two new 10-membered anthraquinone-fused enediynes, yangpumicin (YPM) F (6) and G (7), together with five known congeners YPM A-E (1-5), from Micromonospora yangpuensis DSM 45577. YPM F (6) and G (7) showed strong cytotoxicity against the tested human cancer cell lines, as well as activity against several Gram-positive and Gram-negative pathogens. The 1,2-diols in 6 and 7 promise to enable new linker chemistry for the development of YPM-based ADCs.

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“…1 The enediynes are some of the most potent natural products in existence to date, with subnanomolar inhibitory concentrations (IC 50 s) against a broad panel of cancer cell lines. 3,6 Although too toxic for direct use as chemotherapeutic agents, the enediynes have proven highly efficacious for anticancer therapy when delivered using polymer-based or antibody-directed systems. NCS as a polymer drug conjugate (SMANCS) has been marketed since 1994 for the treatment of certain types of leukemia and hepatoma.…”

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confidence: 99%

“…Other ADCs using C-1027 (also known as lidamycin) 8 and UCM as payloads are currently in various stages of preclinical and clinical studies. 6 It is remarkable that four of the 12 known enediynes have been translated into clinical drugs or are in preclinical development, representing an extraordinary success rate of 33%.…”

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Genome Mining of Micromonospora yangpuensis DSM 45577 as a Producer of an Anthraquinone-Fused Enediyne

et al. 2017

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A new anthraquinone-fused enediyne, yangpumicin A (YPM A, 1), along with four Bergman cyclization congeners (YPM B–E, 2–5), was isolated from Micromonospora yangpuensis DSM 45577 after mining enediyne biosynthetic gene clusters from public actinobacterial genome databases and prioritizing the hits by an enediyne genome neighborhood network analysis for discovery. YPM A is potent against a broad spectrum of human cancer cell lines. The discovery of 1 provides new opportunities for the functionalization of enediynes to develop new conjugation chemistries for antibody—drug conjugates.

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ChemInform Abstract: Enediynes: Exploration of Microbial Genomics to Discover New Anticancer Drug Leads

Abstract: Review: 57 refs.

Cited by 12 publications

References 1 publication

Complete Genome of Micromonospora sp. Strain B006 Reveals Biosynthetic Potential of a Lake Michigan Actinomycete

Complete Genome of Micromonospora sp. Strain B006 Reveals Biosynthetic Potential of a Lake Michigan Actinomycete

Yangpumicins F and G, Enediyne Congeners from Micromonospora yangpuensis DSM 45577

Genome Mining of Micromonospora yangpuensis DSM 45577 as a Producer of an Anthraquinone-Fused Enediyne

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