title: Imaging cellular distribution of Bcl inhibitors using small molecule drug conjugates.
abstract: Overexpression of anti-apoptotic proteins such as Bcl-2 is a cellular mechanism to evade apoptosis; consequently, Bcl-2 inhibitors are being developed as anticancer agents. In this work, we have synthesized a fluorescent version of ABT-199 in an effort to visualize a drug surrogate by high resolution imaging. We show that this fluorescent conjugate has comparable Bcl-2 binding efficacy and cell line potency to the parent compound and can be used as an imaging agent in several cancer cell types. We anticipate that this agent will be a valuable tool for studying the single-cell distribution and pharmacokinetics of ABT-199 as well the broader group of BH3-mimetics.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital , 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Giedt
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Sprachman
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D017209:Apoptosis; D001692:Biological Transport; D001896:Boron Compounds / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008958:Models, Molecular; D057054:Molecular Imaging / Q000379:methods*; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005456:Fluorescent Dyes; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax