Novel advances in biotransformation and bioactivation research-2020 year in review

This annual review is the sixth of its kind since 2016 (see references). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation and bioactivation. These fields are constantly evolving with new molecular structures and discoveries of corresponding pathways for metabolism that impact relevant drug development with respect to efficacy and safety. Based on the selected articles, we created three sections: (1) drug design, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation and safety (Table 1). Unlike in years past, more biotransformation experts have joined and contributed to this effort while striving to maintain a balance of authors from academic and industry settings. Table 1. Articles covered in this review. TitleFirst authorSourceDrug design1Metabolic and pharmaceutical aspects of fluorinated compoundsBM JohnsonJ Med Chem 63: 6315-6386, 20202Effective application of metabolite profiling in drug design and discoveryMA CernyJ Med Chem 63: 6387-6406, 20203Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applicationsL GoracciJ Med Chem 63: 11615-11638, 20204Late-stage lead diversification coupled with quantitative nuclear magnetic resonance spectroscopy to identify new structure-activity relationship vectors at nanomole-scale synthesis: application to loratidine, a human histamine H1 receptor inverse agonistMS LallJ. Med. Chem 63: 7268-7292, 20205GLORYx: prediction of the metabolites resulting from phase 1 and Phase 2 biotransformations of xenobioticsChristina de Bruyn KopsChem Res Toxicol 34: 286-299, 2021Metabolites & drug metabolizing enzymes6Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202.P. KorprasertthawornBiochem Pharmacol 169: 113616, 20197Highly selective inhibition of tyrosine kinase (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165ST Wrobleski STJ Med Chem 62: 8973-8995, 20198Discovery of a Novel deaminated metabolite of a single-stranded oligonucleotide in vivo by mass spectrometryJing LiBioanalysis 11: 1955-1966, 20199In vitro metabolism of 2 '-ribose unmodified and modified phosphorothioate oligonucleotide therapeutics using liquid chromatography mass spectrometryJaeah KimBiomedical Chromatography 34: e4839, 202010Excretion, mass balance, and metabolism of [C-14]LY3202626 in humans: an interplay of microbial reduction, reabsorption, and aldehyde oxidase oxidation that leads to an extended excretion profileK KatyayanDrug Metab Dispos 48: 698-707, 202011Novel homodimer metabolites of GDC-0994 via cytochrome P450-catalyed radical couplingRH TakahashiDrug Metab Dispos 48: 521-527, 202012Metabolism and disposition of volanesorsen, a 2'- O-(2 methoxyethyl) antisense oligonucleotide, across species.N PostDrug Metab Dispos 47: 1164-1173, 2019Bioactivation and safety13Novel o-toluidine metabolite in rat urine associated with urinary bladder carcinogenesisY TajimaChem Res Toxicol 33: 1907-1914, 202014Identifying cysteine, N-Acetylcysteine, and glutathione conjugates as novel metabolites of aristolochic acid I: emergence of a new detoxifying pathwayJ ZhangChem Res Toxicol. 33: 1374-1381, 202015Significance of multiple bioactivation pathways for meclofenamate as revealed through modeling and reaction kineticsMA SchleiffDrug Metab Dispos 49: 133-141, 202116Detoxication versus bioactivation pathways of lapatinib in vitro: UGT1A1 catalyzes the hepatic glucuronidation of debenzylated lapatinib. DT Nardone-WhiteDrug Metab Dispos 49: 233-244, 202117Discovery of JNJ-63576253: a clinical stage androgen receptor antagonist for F877L mutant and wild-type castration-resistant prostate cancer (mCRPC)Z ZhangJ Med Chem 64: 909-924, 202118Bioactivation of alpha,beta-unsaturated carboxylic acids through acyl-glucuronidationT MulderDrug Metab Dispos 48: 819-829, 202019Strategies to mitigate the bioactivation of aryl aminesC ZhangChem Res Tox 33: 1950 - 1959, 202020Investigation of clozapine and olanzapine reactive metabolite formation and protein binding by liquid chromatography-tandem mass spectrometryT GeibChem Res Tox 33: 2420-2431, 202021Application of a rat liver drug bioactivation transcriptional response assay early in drug development that informs chemically reactive metabolite formation and potential for drug-induced liver injuryJJ MonroeToxicol Sci 177: 281-299, 2020