Synthesis, biological evaluation, and structure-activity relationships of a novel class of apurinic/apyrimidinic endonuclease 1 inhibitors.

Therapeutic Approaches
Medicinal Chemistry


APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for ≥95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anticancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogues exhibit single-digit micromolar activity against the purified APE1 enzyme and comparable activity in HeLa whole cell extract assays and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice.


Rai Bantukallu, Ganesha; Vyjayanti, Vaddadi N; Dorjsuren, Dorjbal; Simeonov, Anton; Jadhav, Ajit; Wilson, David M; Maloney, David J;


  • Animals
  • Antineoplastic Agents/ chemical synthesis
  • Antineoplastic Agents/ pharmacokinetics
  • Antineoplastic Agents/ pharmacology
  • Antineoplastic Agents, Alkylating/ pharmacology
  • Benzothiazoles/ chemical synthesis
  • Benzothiazoles/ pharmacokinetics
  • Benzothiazoles/ pharmacology
  • Brain/ metabolism
  • Cell Extracts
  • DNA-(Apurinic or Apyrimidinic Site) Lyase/ antagonists & inhibitors
  • Dacarbazine/ analogs & derivatives
  • Dacarbazine/ pharmacology
  • Drug Synergism
  • HeLa Cells
  • Humans
  • Injections, Intraperitoneal
  • Methyl Methanesulfonate/ pharmacology
  • Mice
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Thiophenes/ chemical synthesis
  • Thiophenes/ pharmacokinetics
  • Thiophenes/ pharmacology
  • Tissue Distribution

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