![]() ![]() J Biol Chem 2012), both in the mitochondrial and nuclear genomes (Das et al., Proc Natl Acad Sci USA 2010) and that knocking out TDP1 results in a neurological phenotype in drosophila (Guo et al Proc Natl Acad Sci USA 2014). Pommier revealed that TDP1 repairs a broad range of 3'-blocking lesions in addition to TOP1 (Murai et al. While studying the tyrosyl-DNA-phosphodiesterase (TDP1 and TDP2) repair pathways for the excision of topoisomerases from DNA, Dr. J Biol Chem 2014 Huang et al., J Biol Chem 2015 Huang et al EMBO J 2017 2018). Pommier demonstrated that misincorporated ribonucleotides (the most frequent DNA alteration) trap topoisomerases, which convert them to toxic and mutagenic nicks by TOP1 (Kim et al. He was the first to show that topoisomerases are trapped by DNA damage (by oxidative base lesions, base alkylation, DNA nicks) (Pourquier et al. Pommier has profoundly contributed to the elucidation of the repair pathways for topoisomerase-=induced DNA damage (Pommier et al., Nat Rev Mol Cell Biol 2016 Sun et al. This was critical for the clinical development of Yondelis. Pommier also discovered that the natural compound, ecteinascidin 743 (commercialized as Yondelis) and its analog trabectedin acts by alkylating DNA and killing cancer cells by trapping transcription-coupled nucleotide excision repair (TC-NER) (Takebayashi et al, Nature Med 2001). J Med Chem 2005) and extended it to macromolecular complexes involving proteins and protein-RNA complexes beyond topoisomerases (Pommier et al. He demonstrated the interfacial inhibitor mechanism by co-crystal studies (Ionaviciu et al. Nucleic Acids Res 1990 Pommier et al., Nucleic Acids Res 1991 Pommier et al. Pommier conceptualized the "interfacial inhibitors" mechanism based on his finding that DNA topoisomerase inhibitors act by trapping topoisomerase-DNA complexes (Capranico et al. Pommier's recent studies show that precision therapeutics can be enacted with TOP1 inhibitors in patients with tumors with homologous recombination deficiency (HRD including BRCA1/2) and expressing high Schlafen 11 (SLFN11) (Thomas & Pommier, Clin Cancer Res 2019 Coussy et al, Sci Transl Med. Based on their promising clinical activity and their superior medicinal properties over the camptothecins, the indenoisoquinolines represent the first non-camptothecin TOP1 inhibitors for the treatment of cancers. 2018) and in PDX models of triple negative breast cancers (TNBC) (Coussy et al, Sci Transl Med. All show potent activity in the Comparative Oncology Trial Consortium (COTC) (Burton, J. Three of his indenoisoquinoline TOP1 inhibitors are in Phase 1/2 clinical development (Thomas & Pommier, Clin Cancer Res 2019): LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744. et al, Nat Rev Mol Cell Biol 2016 Thomas & Pommier, Clin Cancer Res 2019). Pommier is internationally recognized for his contributions to the molecular pharmacology of topoisomerase inhibitors, and for the discovery and development of the non-camptothecin topoisomerase I (TOP1) inhibitors (Pommier, Y. ![]()
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