Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors

Gangloff, Anthony R.; Brown, Jason W.; Jong, Ron de; Dougan, D.R.; Grimshaw, Charles E.; Hixon, Mark S.; Jennings, Andy; Kamran, Ruhi; Kir'yanov, A. A.; O’Connell, Shawn M.; Taylor, Ewan R.; Vu, Phong

doi:10.1016/j.bmcl.2013.06.055

Cited by 29 publications

(18 citation statements)

References 11 publications

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“…2B) (PDB ID: 1UK0) . Several other preclinical inhibitors, for which structural data are available, also exhibit a similar binding mode that involves secondary contacts in the adenine-ribose-binding subsite Kinoshita et al, 2004;Miyashiro et al, 2009;Gangloff et al, 2013;Ye et al, 2013;Patel et al, 2014). From the chemical scaffold and binding mode reported in the tankyrase 2 cocrystal structure (Narwal et al, 2012), olaparib, while bound to the nicotinamide pocket via a phthalazinone core, also likely has both diacylpiperazine and cyclopropyl moieties reaching deeply into the adenine-ribose-binding pocket.…”

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 97%

“…(C) Superpositions of the 33 PARP1 CAT domain structures from PDB indicate that the D-loop residue, Tyr889, can assume multiple side-chain conformations. Binding of a rigid stereospecific inhibitor (e.g., talazoparib) may sterically restrict the side-chain flexibility (PDB IDs: 4PJT, 4GV7, 4HHY, 4HHZ, 4L6S, 4DQY, 3GN7, 3L3L, 3L3M, 3GJW, 2RD6, 1WOK, 1UK0, and 1UK1) Kinoshita et al, 2004;Iwashita et al, 2005;Miyashiro et al, 2009;Gandhi et al, 2010;Penning et al, 2010;Langelier et al, 2012;Gangloff et al, 2013;Lindgren et al, 2013;Ye et al, 2013;Aoyagi-Scharber et al, 2014). (Ruf et al, 1998) and well characterized as a sequence-diverse element in the PARP superfamily Papeo et al, 2013;Steffen et al, 2013), may also contribute to the protein dynamics of the CAT domain that are implicated in the putative inhibitor-induced reverse-allosteric signaling.…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

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Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

192

188

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 97%

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

192

188

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show abstract

“…The nicotinamide binding site of the substrate was close to L helix as well as c and d strands. Six reported ligand-bound PARP-1 crystal structures (PDB Ids: 4HHY (Ye et al, 2013), 3L3M (Penning et al, 2010), 3L3L , 2RD6, 4L6S (Gangloff et al, 2013), and 3GN7) were aligned with each other by the help of Align Protein Structure tool of Maestro. Analyses of the aligned structures revealed that all ligands are superimposed with each other almost perfectly with respect to their nicotinamide-mimicking moieties (Figure 3(A)).…”

Section: Resultsmentioning

confidence: 99%

“…In order to substantiate these facts, the docked poses of the compounds were analyzed on the basis of Site Maps generated at the active site of the PARP-1 enzyme. Six aligned X-ray crystal structures of human PARP-1 (PDB Ids: 4HHY (Ye et al, 2013), 3L3 M (Penning et al, 2010), 3L3L , 2RD6, 4L6S (Gangloff et al, 2013), and 3GN7) were used to generate SiteMaps. The ligand bound pocket of these protein structures showed the highest druggability (SiteScore: 1.037, Dscore; 1.050, size: 339 and volume: 1173.06).…”

Section: Molecular Docking and Binding Energy Predictionmentioning

confidence: 99%

Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validatedin silico modeling techniques and molecular dynamics simulation

Halder

Saha

et al. 2014

Journal of Biomolecular Structure and Dynamics

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Inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) enzyme are useful for the treatment of various diseases including cancer. Comparative in silico studies were performed on different ligand-based (2D-QSAR, Kernel-based partial least square (KPLS) analysis, Pharmacophore Search Engine (PHASE) pharmacophore mapping), and structure-based (molecular docking, MM-GBSA analyses, Gaussian-based 3D-QSAR analyses on docked poses) modeling techniques to explore the structure-activity relationship of a diverse set of PARP-1 inhibitors. Two-dimensional (2D)-QSAR highlighted the importance of charge topological index (JGI7), fractional polar surface area (JursFPSA3), and connectivity index (CIC2) along with different molecular fragments. Favorable and unfavorable fingerprints were demonstrated in KPLS analysis, whereas important pharmacophore features (one acceptor, one donor, and two ring aromatic) along with favorable and unfavorable field effects were demonstrated in PHASE-based pharmacophore model. MM-GBSA analyses revealed significance of different polar, non-polar, and solvation energies. Docking-based alignment of ligands was used to perform Gaussian-based 3D-QSAR study that further demonstrated importance of different field effects. Overall, it was found that polar interactions (hydrogen bonding, bridged hydrogen bonding, and pi-cation) play major roles for higher activity. Steric groups increase the total contact surface area but it should have higher fractional polar surface area to adjust solvation energy. Structure-based pharmacophore mapping spotted the positive ionizable feature of ligands as the most important feature for discriminating highly active compounds from inactives. Molecular dynamics simulation, conducted on highly active ligands, described the dynamic behaviors of the protein complexes and supported the interpretations obtained from other modeling analyses. The current study may be useful for designing PARP-1 inhibitors.

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“…Similar to other PARP-1 inhibitors, docking of DHBF-7-carboxamide (compound 3 ) within the catalytic site of human PARP-1 (PDB code 4L6S) 32 (Figure 1) revealed that the carbonyl oxygen atom formed a hydrogen bond with the side chain hydroxyl group of Ser904 (C=O···HO-Ser904, 1.91 Å) and backbone −NH of Gly863 (C=O···HN-Gly863, 2.09 Å) while the carboxamide hydrogen atom entered into hydrogen bonding interaction with the backbone carbonyl oxygen atom of Gly863 (NH···O=C-Gly863, 1.92 Å). We observed formation of an intramolecular hydrogen bond between the carboxamide hydrogen atoms and the ether oxygen atom of the DHBF-7-carboxamide that results in the formation of pseudotricyclic ring and restriction of the carboxamide moiety.…”

Section: Results and Discussionmentioning

confidence: 99%

Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

et al. 2014

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Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66–68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (−)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.

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Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors

Cited by 29 publications

References 11 publications

Trapping Poly(ADP-Ribose) Polymerase

Trapping Poly(ADP-Ribose) Polymerase

Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validatedin silico modeling techniques and molecular dynamics simulation

Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

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