DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

Abstract

Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J. ; Golding , B. T. ; Griffin , R. J. ; Hardcastle , I. R. ; Richardson , C. ; Rigoreau , L. ; Smith , G. C. M. Bioorg. Med. Chem. Lett. 2004 , 14 , 6083 - 6087) as a potent inhibitor (IC₅₀ = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH₂)(n)NR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure-activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC₅₀ = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

“…Replacement of the chromen-4-one scaffold by the isosteric pyrimidoisoquinolinone structure gave equipotent compounds (8; IC 50 =0.28 µM) [22]. Multiple studies have revealed that 6 acts in vitro as a radiosensitiser, [23] and as a chemo-potentiator of topoisomerase II (TOP2) poisons in human leukaemia cell lines [24].…”

“…VX-984 (22), disclosed by Vertex Pharmaceuticals, is a DNA-PK inhibitor currently undergoing a phase I clinical study, in combination with pegylated liposomal doxorubicin in patients with advanced solid tumours or lymphomas. Compound 22 has an IC 50 of 88 ± 64 nM for inhibition of DNA-PKcs autophosphorylation (Ser2056) in A549 lung cancer cells, with good selectivity versus other PI3K family members [40] …”

Selective radiosensitization of hypoxic cells using BCCA621C: a novel hypoxia activated prodrug targeting DNA-dependent protein kinase

“…It is well established that genetic deficiency or inhibition of DNA-PK results in radiosensitivity of oxygenated cells [18,19,[36][37][38][39][40].…”

Disruption of Protein–DNA Interactions: An Opportunity for Cancer Chemotherapy

“…These data support the possibility that NU7441 is an effective SMI of DNA-PK and in combination treatment with current chemotherapeutic regimens, such as IR or etoposide treatment, a decrease in repair would result in an increase in treatment efficacy. Continued development of both classes of inhibitors including NU7613 continue to target the ATP binding pocket of DNA-PK and result in increased potency and selectivity while also increasing cellular activity (Clapham et al, 2011;Cano et al, 2010;sage-El et al, 2008;Hollick et al, 2007;Griffin et al, 2005), however, their true utility as therapeutic agents awaits clinical assessment.…”