8. Indenos Overview, Mechanisms of Action, & PK

• Overview
  • DNA Topoisomerases: Structure, Function, and Mechanism (Champoux 2001)
  • Synthesis of New Indeno[1,2-c]isoquinolines:  Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors (Cushman 2000)
  • Design and Synthesis of Indenoisoquinolines Targeting Topoisomerase I and Other Biological Macromolecules for Cancer Chemotherapy (Cushman 2021)
  • Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I (Han 2024)
  • The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives (Pommier 2009)
  • Novel clinical indenoisoquinoline topoisomerase I inhibitors: a twist around the camptothecins (Pommier 2018)
  • Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors (Marzi 2018)
  • 7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents (Kiselev  2011)
  • Optimization of the Lactam Side Chain of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells (Kiselev E, M Cushman Y Pommier et al.   2014)
  • Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I
  • (Elsayed 2017)

• Mechanisms of Action

• • Differential Induction of Topoisomerase I-DNA Cleavage Complexes by the Indenoisoquinoline MJ-III-65 (NSC 706744) and Camptothecin: Base Sequence Analysis and Activity against Camptothecin- Resistant Topoisomerases I (Antony 2005)

• • Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison (Antony 2005)
  • Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity (Antony 2006)
  • Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance (Antony  2007)
  • ATR Inhibitors VE-821 and VX-970 Sensitize Cancer Cells to Topoisomerase I Inhibitors by Disabling DNA Replication Initiation and Fork Elongation Responses (Josse 2014)
  • Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC (Wang 2019)

• Top1 Inhibition

• • Topoisomerase I inhibitors: Challenges, progress and the road ahead (Talukdar 2022)

• • Targeting Topoisomerase I in the Era of Precision Medicine (Thomas 2019)

• • Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl–DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl–DNA Phosphodiesterase 2 (Tdp2) (Wang 2017)

• Pharmacokinetics and Pharmacodynamics
  • Phase I pharmacokinetics and pharmacodynamics of a novel indenoisoquinoline topoisomerase 1 (TOP1) inhibitor, LMP400, administered on a daily x 5 schedule (Beumer 2014)  

• • Pharmacokinetics and pharmacodynamics of indenoisoquinoline LMP400 (Indotecan) in BALB/c female mice bearing CT-26 colon tumors (Guo 2015)

• • Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs (Muzzio 2015)

• • Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors (Kummar 2016)

• • Plasma and tumor pharmacokinetics of IV LMP400, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study (Eisman 2014)

• Potential Biomarkers

• • Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets (Gilbert 2011)

• • DNA-Targeted Precision Medicine; Have We Been Caught Sleeping? (Reinhold 2017)

• • Targeting Topoisomerase I in the Era of Precision Medicine (Thomas 2019)

• • The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib (Marzi 2019)

• • BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers (Coussy 2020)

• • Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11 (Jo 2021)

• • Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma (Alzial2022)

• • SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression (Fischietti 2022) 

• • c-Myc Is Required for Maintenance of Glioma Cancer Stem Cells (Wang 2008)

• • p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation (Zheng 2008)