Topoisomerase 1 Dmel_CG6146

Overview

Topoisomerase 1 Dmel_CG6146 (Wikidata: Q29814717) is the Drosophila melanogaster ortholog of human DNA topoisomerase I (TOP1), encoded by the CG6146 gene. Topoisomerase I is an essential nuclear enzyme that resolves topological stress in DNA by transiently cleaving a single strand of the double helix, allowing controlled rotation around the intact strand, and then religating the nick. This catalytic cycle is indispensable for the progression of DNA replication forks and RNA polymerase complexes during transcription. The enzyme forms a transient covalent intermediate known as the topoisomerase I cleavage complex (TOP1cc), in which a tyrosine residue in the active site is covalently linked to the 3′ end of the cleaved DNA strand. In the context of cancer biology and pharmacology, TOP1 is one of the most validated antitumor drug targets: small-molecule inhibitors that stabilize or trap the TOP1cc prevent religation, converting a normal enzymatic intermediate into a DNA double-strand break that triggers apoptosis in rapidly dividing cells. The Drosophila CG6146 protein is highly conserved with its human counterpart and has served as a tractable genetic and biochemical model for understanding TOP1 function, inhibitor sensitivity, and DNA damage response pathways.

Focus of Latest Publications

Recent publications on Topoisomerase 1 Dmel_CG6146 have focused primarily on its role as a therapeutic target in anticancer drug discovery, especially in the development of new topoisomerase I inhibitors, degraders, and payload-based delivery systems. Several studies reported the design and biological evaluation of novel small molecules that inhibit TOP1 activity and induce DNA damage, cell-cycle arrest, and apoptosis in cancer cells. These included flavonolactam derivatives, fused pyridopyrimidine compounds, benzothiophene and benzothienopyran analogs, sophoridine and matrine derivatives, and anthra[2,3-b]furan-5,10-diones, many of which showed potent antiproliferative activity in vitro and, in some cases, antitumor efficacy in xenograft models.

A recurring theme was the optimization of TOP1-directed chemistry to improve potency, selectivity, and drug-like properties. One study reprogrammed aromatic camptothecins into TOP1 degraders by combining hydrophobic tagging with supramolecular self-assembly, producing a lead candidate that promoted proteasome-dependent TOP1 degradation and showed superior tumor regression compared with irinotecan in xenograft models. Other work examined SN-38-based constructs, including an antibody-drug conjugate and a bifunctional SN-38–nitrogen mustard conjugate, both of which were designed to enhance delivery or combine TOP1 inhibition with additional DNA-damaging mechanisms. The SN-38 conjugate studies reported improved solubility, TOP1 inhibition and degradation, DNA crosslinking, and strong antitumor activity without apparent toxicity in mouse models.

Additional publications explored resistance mechanisms and combination strategies linked to TOP1-targeted therapy. In colorectal cancer, IMMU132 was studied as an anti-TROP2 ADC delivering SN-38 to induce TOP1-mediated DNA damage, while also suppressing the PERK-eIF2α-ATF4 stress-response axis; combining it with a PERK inhibitor enhanced suppression of ER stress and the Wnt/β-catenin pathway. In cervical cancer, a TDP1 inhibitor was developed to potentiate topotecan, a TOP1 inhibitor, by blocking DNA repair and increasing DNA damage, apoptosis, and S-phase arrest. These findings underscore the importance of pairing TOP1-targeted agents with modulators of DNA repair or stress-adaptation pathways to overcome resistance.

Methodologically, the studies used a broad toolkit including enzyme inhibition assays, DNA relaxation and supercoiling assays, molecular docking and molecular dynamics simulations, cytotoxicity screening across cancer cell lines, and in vivo xenograft or tumor-bearing mouse models. Across these reports, TOP1 inhibition was repeatedly associated with DNA damage, G2/M or G0/G1 arrest, apoptosis, and in some cases modulation of B-cell lymphoma 2, TP53, ferroptosis, or cGAS-STING signaling. Collectively, the recent literature portrays Topoisomerase 1 Dmel_CG6146 as a central and versatile target for both direct inhibition and more advanced therapeutic strategies such as degradation, conjugate design, and combination therapy.