Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors sensitize tumors to DNA-damaging agents and also inhibit the growth of cancers with BRCA1/2 loss. The synthesis, enzymatic, cellular & pharmacodynamic activities of a series of PARP-1 inhibitors with a novel 1,4-benzoxazin-3-one scaffold are described. A small screening fragment was elaborated through structure-based drug design, ultimately producing several vectors for optimization including interaction with a hydrophobic shelf and extension into the back pocket. The synthesis of 40 compounds is outlined. Optimization of the screening fragment improved LLE's to > 5.0. Several of the resulting inhibitors displayed greater than 1000-fold enhancement of temozolimide (TMZ)-mediated DNA damage in cellular assays. Pharmacodynamic effects in SW620 tumor bearing nude mice demonstrated inhibition of poly-ADP-ribosylation through 24 hours following a single dose.
PARP-1 Binding Potencies and Efficiency Metrics for Benzoxazinones 2-3CmpdaR1R2R3PARP-1 Kd (uM)PARP-1 LLE2aHHH>500-2dMeHH322.32gMeMeH>500-2bHH6-Formyl1702.02fHH6-Ethyl1002.03aHH6-PhenylNHCH2262.23bHH6-BenzylNHCH2113.53cMeH6-BenzylNHCH25.23.23dHH6- (4-(Me2N)piperidine)CH2153.03eMeH6- (4-(Me2N)piperidine)CH20.0964.63fHH6- (4-(Phenyl)piperidine)CH20.2963.43gMeH6- (4-(Phenyl)piperidine)CH20.0463.73hMeH7- (4-(Phenyl)piperidine)CH2101.43iHH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH20.0154.53jMeH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH20.0034.93kMeH7- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH21000.23lEtH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH21000.1 Enzymatic and Cellular Activity for Benzoxazinones 10CmpdR1R2R3PARP-1 IC50 (nM)Cell EC50 w/TMZ (uM)Cell EC50 w/o TMZ (uM)Cell PF5010aHHMe2915141.010bHHEt2215422.810cHClEt1841002010dMeHMe1711756.810eMeHEt699410.410fMeHcPr3351002010gOMeHMe29272519.310hOmeHEt23161519.410iOMeHcPr30161621010jMeClMe4914453.210kMeClEt8914473.410lMeClcPr760.0143430010mMeMeMe389788.710nMeMeEt569556.110oMeMecPr52181005.610pOmeMeMe360.06100166710qOMeMeEt320.0144440010rOMeMecPr1470.0277385010sOEtMeMe350.0226130010tOEtMeEt550.02100500010uOEtMecPr410.021005000ABT-888---16316056AZD-2281---60.0616660MK-4827---350.2031160
Citation Format: Anthony R. Gangloff, Jason Brown, Ron De Jong, Philip Erickson, Charles Grimshaw, Mark Hixon, Andy Jennings, Ruhi Kamran, Andre Kiryanov, Shawn O'Connell, Ewan Taylor, Phong Vu. Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-Ribose)polymerase inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5676. doi:10.1158/1538-7445.AM2013-5676
