title: Synthesis, biological evaluation, and structure-activity relationships of a novel class of apurinic/apyrimidinic endonuclease 1 inhibitors.
abstract: 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.
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892-3370, USA.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Vaddadi N
authors.initials: VN
authors.lastname: Vyjayanti
authors.forename: Dorjbal
authors.initials: D
authors.lastname: Dorjsuren
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002457:Cell Extracts; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D052160:Benzothiazoles; D002457:Cell Extracts; C574638:N-(3-(benzo(d)thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridin-2-yl)acetamide; D054852:Small Molecule Libraries; D013876:Thiophenes; D003606:Dacarbazine; D008741:Methyl Methanesulfonate; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D000077204:Temozolomide