A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach

Journal of Medicinal Chemistry

Volumn 58, Issue 6, 2015, Pages 2779-2798

  Milite, Ciro ^a   Feoli, Alessandra ^a   Sasaki, Kazuki ^b,c   La Pietra, Valeria ^d   Balzano, Amodio Luca ^a   Marinelli, Luciana ^d   Mai, Antonello ^e   Novellino, Ettore ^d   Castellano, Sabrina ^a,f   Tosco, Alessandra ^a   Sbardella, Gianluca ^a  

^a UNIVERSITY OF SALERNO   (Italy)

^b RIKEN   (Japan)

^c JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^d UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^e SAPIENZA UNIVERSITY OF ROME   (Italy)

^f UNIVERSITY OF SALERNO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

1,3 DIALLYL (4 HYDROXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIALLYL 5 (3 HYDROXY 4 METHOXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIALLYL 5 (3,4 DIHYDROXYBENZOYL)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIALLYL 5 (3,4 DIHYDROXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (2 ETHOXYBENZO[D][1,3]DIOXOLE 5 CARBONYL) PYRIMIDINE 2,4,6(1,H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (3 HYDROXY 4 METHOXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (3,4 DIHYDROXYBENZOYL)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (3,4 DIHYDROXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (4 HYDROXY 3 METHOXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (4 HYDROXYBENZOYL)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIBENZYL 5 (4 HYDROXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIISOBUTYL 5 (3 HYDROXY 4 METHOXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIISOBUTYL 5 (4 HYDROXY 3 METHOXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIISOBUTYL 5 (4 HYDROXYBENZOYL)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 1,3 DIISOBUTYL 5 (4 HYDROXYBENZYLIDENE)PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 (3,4 DIHYDROXYBENZOYL) 1,3 DIISOBUTYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 (3,4 DIHYDROXYBENZYLIDENE) 1,3 DIISOBUTYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 (4 ACETOXYBENZOYL) 1,3 DIALLYL PYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 (4 ACETOXYBENZOYL) 1,3 DIBENZYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 (4 ACETOXYBENZOYL) 1,3 DIISOBUTYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 BENZOYL 1,3 DIALLYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 BENZOYL 1,3 DIBENZYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 BENZOYL 1,3 DIISOBUTYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 BENZYLIDENE 1,3 DIALLYLPYRIMIDINE 2,4,6(1H,3H,5) TRIONE; 5 BENZYLIDENE 1,3 DIBENZYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; 5 BENZYLIDENE 1,3 DIISOBUTYLPYRIMIDINE 2,4,6(1H,3H,5H) TRIONE; ACYLTRANSFERASE INHIBITOR; ANTINEOPLASTIC AGENT; KAT3 HISTONE ACETYLTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; ENZYME INHIBITOR; HISTONE; HISTONE ACETYLTRANSFERASE PCAF; LYSINE;

ARTICLE; CELL CYCLE G1 PHASE; CELL MEMBRANE PERMEABILITY; CELL VIABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HYDROGEN BOND; IC50; MICROWAVE IRRADIATION; MOLECULAR MODEL; PROTON NUCLEAR MAGNETIC RESONANCE; REDUCTION; SURFACE PLASMON RESONANCE; WESTERN BLOTTING; ACETYLATION; ANTAGONISTS AND INHIBITORS; CELL CYCLE CHECKPOINT; CELL SURVIVAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; LEUKEMIA; METABOLISM; TUMOR CELL LINE;

ACETYLATION; ANTINEOPLASTIC AGENTS; CELL CYCLE CHECKPOINTS; CELL LINE, TUMOR; CELL SURVIVAL; ENZYME INHIBITORS; HISTONES; HUMANS; LEUKEMIA; LYSINE; MODELS, MOLECULAR; P300-CBP TRANSCRIPTION FACTORS;

EID: 84925957014     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5019687     Document Type: Article

References (78)

1. Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis Proc. Natl. Acad. Sci. U. S. A. 1964, 51, 786-794
2. Gorisch, S. M.; Wachsmuth, M.; Toth, K. F.; Lichter, P.; Rippe, K. Histone acetylation increases chromatin accessibility J. Cell Sci. 2005, 118, 5825-5834
3. Bannister, A. J.; Kouzarides, T. Regulation of chromatin by histone modifications Cell Res. 2011, 21, 381-395
4. Allis, C. D.; Berger, S. L.; Cote, J.; Dent, S.; Jenuwien, T.; Kouzarides, T.; Pillus, L.; Reinberg, D.; Shi, Y.; Shiekhattar, R.; Shilatifard, A.; Workman, J.; Zhang, Y. New nomenclature for chromatin-modifying enzymes Cell 2007, 131, 633-636
5. Hodawadekar, S. C.; Marmorstein, R. Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design Oncogene 2007, 26, 5528-5540
6. Lee, K. K.; Workman, J. L. Histone acetyltransferase complexes: one size doesnt fit all Nature Rev. Mol. Cell Biol. 2007, 8, 284-295
7. Chrivia, J. C.; Kwok, R. P. S.; Lamb, N.; Hagiwara, M.; Montminy, M. R.; Goodman, R. H. Phosphorylated CREB binds specifically to the nuclear protein CBP Nature 1993, 365, 855-859
8. Harlow, E.; Whyte, P.; Franza, B. R.; Schley, C. Association of adenovirus early-region 1A proteins with cellular polypeptides Mol. Cell. Biol. 1986, 6, 1579-1589
9. Bannister, A. J.; Kouzarides, T. The CBP co-activator is a histone acetyltransferase Nature 1996, 384, 641-643
10. Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases Cell 1996, 87, 953-959
11. Liu, X.; Wang, L.; Zhao, K.; Thompson, P. R.; Hwang, Y.; Marmorstein, R.; Cole, P. A. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator Nature 2008, 451, 846-850
12. Petrij, F.; Dorsman, J. C.; Dauwerse, H. G.; Giles, R. H.; Peeters, T.; Hennekam, R. C. M.; Breuning, M. H.; Peters, D. J. M. Rubinstein-Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q36.3;p13.3) Am. J. Med. Genet. 2000, 92, 47-52
13. Bayly, R.; Chuen, L.; Currie, R. A.; Hyndman, B. D.; Casselman, R.; Blobel, G. A.; LeBrun, D. P. E2A-PBX1 Interacts Directly with the KIX Domain of CBP/p300 in the Induction of Proliferation in Primary Hematopoietic Cells J. Biol. Chem. 2004, 279, 55362-55371
14. Morin, R. D.; Mendez-Lago, M.; Mungall, A. J.; Goya, R.; Mungall, K. L.; Corbett, R. D.; Johnson, N. A.; Severson, T. M.; Chiu, R.; Field, M.; Jackman, S.; Krzywinski, M.; Scott, D. W.; Trinh, D. L.; Tamura-Wells, J.; Li, S.; Firme, M. R.; Rogic, S.; Griffith, M.; Chan, S.; Yakovenko, O.; Meyer, I. M.; Zhao, E. Y.; Smailus, D.; Moksa, M.; Chittaranjan, S.; Rimsza, L.; Brooks-Wilson, A.; Spinelli, J. J.; Ben-Neriah, S.; Meissner, B.; Woolcock, B.; Boyle, M.; McDonald, H.; Tam, A.; Zhao, Y.; Delaney, A.; Zeng, T.; Tse, K.; Butterfield, Y.; Birol, I.; Holt, R.; Schein, J.; Horsman, D. E.; Moore, R.; Jones, S. J. M.; Connors, J. M.; Hirst, M.; Gascoyne, R. D.; Marra, M. A. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma Nature 2011, 476, 298-303
15. Borrow, J.; Stanton, V. P.; Andresen, J. M.; Becher, R.; Behm, F. G.; Chaganti, R. S. K.; Civin, C. I.; Disteche, C.; Dube, I.; Frischauf, A. M.; Horsman, D.; Mitelman, F.; Volinia, S.; Watmore, A. E.; Housman, D. E. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein Nature Genet. 1996, 14, 33-41
16. Chaffanet, M.; Gressin, L.; Preudhomme, C.; Soenen-Cornu, V.; Birnbaum, D.; Pébusque, M.-J. MOZ is fused to p300 in an acute monocytic leukemia with t(8;22) Genes, Chromosomes Cancer 2000, 28, 138-144
17. Satake, N.; Ishida, Y.; Otoh, Y.; Hinohara, S.-i.; Kobayashi, H.; Sakashita, A.; Maseki, N.; Kaneko, Y. Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation Genes, Chromosomes Cancer 1997, 20, 60-63
18. Ianculescu, I.; Wu, D.-Y.; Siegmund, K. D.; Stallcup, M. R. Selective Roles for cAMP Response Element-Binding Protein Binding Protein and p300 Protein as Coregulators for Androgen-Regulated Gene Expression in Advanced Prostate Cancer Cells J. Biol. Chem. 2012, 287, 4000-4013
19. Ionov, Y.; Matsui, S.-I.; Cowell, J. K. A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 1273-1278
20. Takeuchi, A.; Shiota, M.; Tatsugami, K.; Yokomizo, A.; Tanaka, S.; Kuroiwa, K.; Eto, M.; Naito, S. p300 mediates cellular resistance to doxorubicin in bladder cancer Mol. Med. Rep. 2012, 5, 173-176
21. Castellano, S.; Milite, C.; Feoli, A.; Viviano, M.; Mai, A.; Novellino, E.; Tosco, A.; Sbardella, G. Identification of Structural Features of 2-Alkylidene-1,3-dicarbonyl Derivatives that Induce Inhibition and/or Activation of Histone Acetyltransferases KAT3B/p300 and KAT2B/PCAF ChemMedChem 2015, 10, 144-157
22. Mantelingu, K.; Reddy, B. A. A.; Swaminathan, V.; Kishore, A. H.; Siddappa, N. B.; Kumar, G. V. P.; Nagashankar, G.; Natesh, N.; Roy, S.; Sadhale, P. P.; Ranga, U.; Narayana, C.; Kundu, T. K. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication Chem. Biol. 2007, 14, 645-657
23. Sadoul, K.; Wang, J.; Diagouraga, B.; Khochbin, S. The tale of protein lysine acetylation in the cytoplasm J. Biomed. Biotechnol. 2011, 2011, 970382
24. Lu, X.; Deng, Y.; Yu, D.; Cao, H.; Wang, L.; Liu, L.; Yu, C.; Zhang, Y.; Guo, X.; Yu, G. Histone Acetyltransferase p300 Mediates Histone Acetylation of PS1 and BACE1 in a Cellular Model of Alzheimers Disease PLoS One 2014, 9, e103067
25. Sananbenesi, F.; Fischer, A. Histone-acetylation: a link of between Alzheimers disease and post-traumatic stress disorder? Front. Neurosci. 2014, 8
26. Valor, L. M.; Viosca, J.; Lopez-Atalaya, J. P.; Barco, A. Lysine Acetyltransferases CBP and p300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders Curr. Pharm. Des. 2013, 19, 5051-64
27. Peixoto, L.; Abel, T. The role of histone acetylation in memory formation and cognitive impairments Neuropsychopharmacology 2013, 38, 62-76
28. Yuan, H.; Reddy, M. A.; Sun, G.; Lanting, L.; Wang, M.; Kato, M.; Natarajan, R. Involvement of p300/CBP and epigenetic histone acetylation in TGF- 1-mediated gene transcription in mesangial cells Am. J. Physiol.: Renal. Physiol. 2013, 304, F601-F613
29. Zhou, X. Y.; Shibusawa, N.; Naik, K.; Porras, D.; Temple, K.; Ou, H.; Kaihara, K.; Roe, M. W.; Brady, M. J.; Wondisford, F. E. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein Nature Med. 2004, 10, 633-637
30. Ban, N.; Yamada, Y.; Someya, Y.; Miyawaki, K.; Ihara, Y.; Hosokawa, M.; Toyokuni, S.; Tsuda, K.; Seino, Y. Hepatocyte Nuclear Factor-1 Recruits the Transcriptional Co-Activator p300 on the GLUT2 Gene Promoter Diabetes 2002, 51, 1409-1418
31. Das, D.; Bandyopadhyay, D.; Bhattacharjee, M.; Banerjee, R. Hydroxyl radical is the major causative factor in stress-induced gastric ulceration Free Radical Biol. Med. 1997, 23, 8-18
32. Wang, Y.; Miao, X.; Liu, Y.; Li, F.; Liu, Q.; Sun, J.; Cai, L. Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases Oxid. Med. Cell. Longevity 2014, 2014, 11
33. Reddy, M. A.; Natarajan, R. Epigenetic mechanisms in diabetic vascular complications Cardiovasc. Res. 2011, 90, 421-429
34. Gusterson, R. J.; Jazrawi, E.; Adcock, I. M.; Latchman, D. S. The Transcriptional Co-activators CREB-binding Protein (CBP) and p300 Play a Critical Role in Cardiac Hypertrophy That Is Dependent on Their Histone Acetyltransferase Activity J. Biol. Chem. 2003, 278, 6838-6847
35. Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P. C.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Muller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E. Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains J. Am. Chem. Soc. 2014, 136, 9308-9319
36. Block, K. M.; Wang, H.; Szabo, L. Z.; Polaske, N. W.; Henchey, L. K.; Dubey, R.; Kushal, S.; Lászlo, C. F.; Makhoul, J.; Song, Z.; Meuillet, E. J.; Olenyuk, B. Z. Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex with Designed Dimeric Epidithiodiketopiperazine J. Am. Chem. Soc. 2009, 131, 18078-18088
37. Majmudar, C. Y.; Højfeldt, J. W.; Arevang, C. J.; Pomerantz, W. C.; Gagnon, J. K.; Schultz, P. J.; Cesa, L. C.; Doss, C. H.; Rowe, S. P.; Vásquez, V.; Tamayo-Castillo, G.; Cierpicki, T.; Brooks, C. L.; Sherman, D. H.; Mapp, A. K. Sekikaic Acid and Lobaric Acid Target a Dynamic Interface of the Coactivator CBP/p300 Angew. Chem., Int. Ed. 2012, 51, 11258-11262
38. Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. Small molecule modulators of histone acetyltransferase p300 J. Biol. Chem. 2003, 278, 19134-19140
39. Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.; Sadhale, P. P.; Kundu, T. K. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression J. Biol. Chem. 2004, 279, 33716-33726
40. Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription J. Biol. Chem. 2004, 279, 51163-51171
41. Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. Inhibition of lysine acetyltransferase KAT3B/p300 activity by a naturally occurring hydroxynaphthoquinone, plumbagin J. Biol. Chem. 2009, 284, 24453-24464
42. Arif, M.; Vedamurthy, B. M.; Choudhari, R.; Ostwal, Y. B.; Mantelingu, K.; Kodaganur, G. S.; Kundu, T. K. Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A Chem. Biol. 2010, 17, 903-913
43. Costi, R.; Di Santo, R.; Artico, M.; Miele, G.; Valentini, P.; Novellino, E.; Cereseto, A. Cinnamoyl compounds as simple molecules that inhibit p300 histone acetyltransferase J. Med. Chem. 2007, 50, 1973-1977
44. Eliseeva, E. D.; Valkov, V.; Jung, M.; Jung, M. O. Characterization of novel inhibitors of histone acetyltransferases Mol. Cancer Ther. 2007, 6, 2391-2398
45. Mai, A.; Cheng, D.; Bedford, M. T.; Valente, S.; Nebbioso, A.; Perrone, A.; Brosch, G.; Sbardella, G.; De Bellis, F.; Miceli, M.; Altucci, L. Epigenetic multiple ligands: mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (sirtuin) inhibitors J. Med. Chem. 2008, 51, 2279-2290
46. Vasudevarao, M. D.; Mizar, P.; Kumari, S.; Mandal, S.; Siddhanta, S.; Swamy, M. M. M.; Kaypee, S.; Kodihalli, R. C.; Banerjee, A.; Narayana, C.; Dasgupta, D.; Kundu, T. K. Naphthoquinones mediated inhibition of lysine acetyltransferase KAT3B/p300, basis for non-toxic inhibitor synthesis J. Biol. Chem. 2014, 289, 7702-7717
47. Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF Mol. Cell 2000, 5, 589-595
48. Bowers, E. M.; Yan, G.; Mukherjee, C.; Orry, A.; Wang, L.; Holbert, M. A.; Crump, N. T.; Hazzalin, C. A.; Liszczak, G.; Yuan, H.; Larocca, C.; Saldanha, S. A.; Abagyan, R.; Sun, Y.; Meyers, D. J.; Marmorstein, R.; Mahadevan, L. C.; Alani, R. M.; Cole, P. A. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor Chem. Biol. 2010, 17, 471-482
49. Dancy, B. M.; Crump, N. T.; Peterson, D. J.; Mukherjee, C.; Bowers, E. M.; Ahn, Y.-H.; Yoshida, M.; Zhang, J.; Mahadevan, L. C.; Meyers, D. J.; Boeke, J. D.; Cole, P. A. Live-cell studies of p300/CBP histone acetyltransferase activity and inhibition ChemBioChem 2012, 13, 2113-2121
50. Arif, M.; Pradhan, S. K.; G R, T.; Vedamurthy, B. M.; Agrawal, S.; Dasgupta, D.; Kundu, T. K. Mechanism of p300 specific histone acetyltransferase inhibition by small molecules J. Med. Chem. 2009, 52, 267-277
51. Pinacho Crisostomo, F. R.; Carrillo, R.; Leon, L. G.; Martin, T.; Padron, J. M.; Martin, V. S. Molecular Simplification in Bioactive Molecules: Formal Synthesis of (+)-Muconin J. Org. Chem. 2006, 71, 2339-2345
52. Sbardella, G.; Castellano, S.; Vicidomini, C.; Rotili, D.; Nebbioso, A.; Miceli, M.; Altucci, L.; Mai, A. Identification of long chain alkylidenemalonates as novel small molecule modulators of histone acetyltransferases Bioorg. Med. Chem. Lett. 2008, 18, 2788-2792
53. Milite, C.; Castellano, S.; Benedetti, R.; Tosco, A.; Ciliberti, C.; Vicidomini, C.; Boully, L.; Franci, G.; Altucci, L.; Mai, A.; Sbardella, G. Modulation of the activity of histone acetyltransferases by long chain alkylidenemalonates (LoCAMs) Bioorg. Med. Chem. 2011, 19, 3690-3701
54. Colussi, C.; Rosati, J.; Straino, S.; Spallotta, F.; Berni, R.; Stilli, D.; Rossi, S.; Musso, E.; Macchi, E.; Mai, A.; Sbardella, G.; Castellano, S.; Chimenti, C.; Frustaci, A.; Nebbioso, A.; Altucci, L.; Capogrossi, M. C.; Gaetano, C. N -Lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 2795-2800
55. Wei, W.; Coelho, C. M.; Li, X.; Marek, R.; Yan, S.; Anderson, S.; Meyers, D.; Mukherjee, C.; Sbardella, G.; Castellano, S.; Milite, C.; Rotili, D.; Mai, A.; Cole, P. A.; Sah, P.; Kobor, M. S.; Bredy, T. W. p300/CBP-associated factor selectively regulates the extinction of conditioned fear J. Neurosci. 2012, 32, 11930-11941
56. Colussi, C.; Scopece, A.; Vitale, S.; Spallotta, F.; Mattiussi, S.; Rosati, J.; Illi, B.; Mai, A.; Castellano, S.; Sbardella, G.; Farsetti, A.; Capogrossi, M. C.; Gaetano, C. P300/CBP associated factor regulates nitroglycerin-dependent arterial relaxation by N -lysine acetylation of contractile proteins Arterioscler., Thromb., Vasc. Biol. 2012, 32, 2435-2443
57. Spallotta, F.; Cencioni, C.; Straino, S.; Sbardella, G.; Castellano, S.; Capogrossi, M. C.; Martelli, F.; Gaetano, C. Enhancement of lysine acetylation accelerates wound repair Commun. Integr. Biol. 2013, 6, e25466
58. Duffy, K. J.; Fitch, D. M.; Jin, J.; Liu, R.; Shaw, A. N.; Wiggall, K. Preparation of N-substituted pyrimidine-trione amino acid derivatives as prolyl hydroxylase inhibitors. WO2007150011A2, 2007.
59. Kirsch, D. R.; Benmohamed, R.; Arvanites, A. C.; Morimoto, R. I.; Xia, G.; Silverman, R. B. Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis. WO2010129665A2, 2010.
60. Xia, G.; Benmohamed, R.; Kim, J.; Arvanites, A. C.; Morimoto, R. I.; Ferrante, R. J.; Kirsch, D. R.; Silverman, R. B. Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis J. Med. Chem. 2011, 54, 2409-2421
61. Weibel, N.; Baszczyk, A.; von Hanisch, C.; Mayor, M.; Pobelov, I.; Wandlowski, T.; Chen, F.; Tao, N. Redox-Active Catechol-Functionalized Molecular Rods: Suitable Protection Groups and Single-Molecule Transport Investigations Eur. J. Org. Chem. 2008, 2008, 136-149
62. Sasaki, K.; Ito, T.; Nishino, N.; Khochbin, S.; Yoshida, M. Real-time imaging of histone H4 hyperacetylation in living cells Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16257-16262
63. Kansy, M.; Senner, F.; Gubernator, K. Physicochemical High Throughput Screening: Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes J. Med. Chem. 1998, 41, 1007-1010
64. Dreassi, E.; Zizzari, A. T.; Falchi, F.; Schenone, S.; Santucci, A.; Maga, G.; Botta, M. Determination of permeability and lipophilicity of pyrazolo-pyrimidine tyrosine kinase inhibitors and correlation with biological data Eur. J. Med. Chem. 2009, 44, 3712-3717
65. Copeland, R. A. Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, 2nd ed.; Wiley-VCH: New York, 2000.
66. Nicoletti, I.; Migliorati, G.; Pagliacci, M. C.; Grignani, F.; Riccardi, C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry J. Immunol. Methods 1991, 139, 271-279
67. Gao, X.-n.; Lin, J.; Ning, Q.-y.; Gao, L.; Yao, Y.-s.; Zhou, J.-h.; Li, Y.-h.; Wang, L.-l.; Yu, L. A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells PLoS One 2013, 8, e55481
68. Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells J. Invest. Dermatol. 2013, 133, 2444-2452
69. Ait-Si-Ali, S.; Polesskaya, A.; Filleur, S.; Ferreira, R.; Duquet, A.; Robin, P.; Vervish, A.; Trouche, D.; Cabon, F.; Harel-Bellan, A. CBP/p300 histone acetyl-transferase activity is important for the G1/S transition Oncogene 2000, 19, 2430-2437
70. Iyer, N. G.; Xian, J.; Chin, S. F.; Bannister, A. J.; Daigo, Y.; Aparicio, S.; Kouzarides, T.; Caldas, C. p300 is required for orderly G1//S transition in human cancer cells Oncogene 2006, 26, 21-29
71. Wohnsland, F.; Faller, B. High-Throughput Permeability pH Profile and High-Throughput Alkane/Water log P with Artificial Membranes J. Med. Chem. 2001, 44, 923-930
72. Sugano, K.; Hamada, H.; Machida, M.; Ushio, H. High Throughput Prediction of Oral Absorption: Improvement of the Composition of the Lipid Solution Used in Parallel Artificial Membrane Permeation Assay J. Biomol. Screening 2001, 6, 189-196
73. Huey, R.; Morris, G. M.; Olson, A. J.; Goodsell, D. S. A semiempirical free energy force field with charge-based desolvation J. Comput. Chem. 2007, 28, 1145-1152
74. Schuttelkopf, A. W.; van Aalten, D. M. F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 1355-1363
75. Solis, F. J.; Wets, R. J. B. Minimization by Random Search Techniques Math. Oper. Res. 1981, 6, 19-30
76. Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes J. Med. Chem. 2006, 49, 6177-6196
77. Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids J. Am. Chem. Soc. 1996, 118, 11225-11236
78. Kaminski, G. A.; Friesner, R. A.; Tirado-Rives, J.; Jorgensen, W. L. Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides J. Phys. Chem. B 2001, 105, 6474-6487