Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)

Journal of Medicinal Chemistry

Volumn 54, Issue 20, 2011, Pages 7105-7126

  Rewcastle, Gordon W ^a,b   Gamage, Swarna A ^a   Flanagan, Jack U ^a,b   Frederick, Raphael ^a,b,c   Denny, William A ^a,b   Baguley, Bruce C ^a,b   Kestell, Philip ^a   Singh, Ripudaman ^a   Kendall, Jackie D ^a,b   Marshall, Elaine S ^a   Lill, Claire L ^a   Lee, Woo Jeong ^b   Kolekar, Sharada ^b   Buchanan, Christina M ^b   Jamieson, Stephen M F ^a,b   Shepherd, Peter R ^b  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

^b UNIVERSITY OF AUCKLAND   (New Zealand)

^c UNIVERSITY OF NAMUR   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 DIFLUOROMETHYLBENZIMIDAZOL 1 YL) 4,6 DIMORPHOLINO 1,3,5 TRIAZINE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; FEMALE; GLIOBLASTOMA; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZIMIDAZOLES; CELL LINE, TUMOR; CELL PROLIFERATION; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HUMANS; ISOENZYMES; MALE; MICE; MICE, KNOCKOUT; MODELS, MOLECULAR; MUTATION; NEOPLASM TRANSPLANTATION; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHORYLATION; SIGNAL TRANSDUCTION; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS; TRIAZINES;

EID: 80054952210     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200688y     Document Type: Article

References (78)

1. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer Nat. Rev. Cancer 2002, 2, 489-501 (Pubitemid 37328931)
2. Cantley, L. C. The phosphoinositide 3-kinase pathway Science 2002, 296, 1655-1657 (Pubitemid 34579158)
3. Shepherd, P. R. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues Acta Physiol. Scand. 2005, 183, 3-12 (Pubitemid 40188032)
4. Shepherd, P. R.; Withers, D. J.; Siddle, K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signaling Biochem. J. 1998, 333, 471-490 (Pubitemid 28398511)
5. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer Nat. Rev. Drug Discovery 2009, 8, 627-644
6. Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signaling Nat. Rev. Mol. Cell Biol. 2010, 11, 329-341
7. Beeton, C. A.; Chance, E. M.; Foukas, L. C.; Shepherd, P. R. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110α and p110β catalytic subunits of class-Ia phosphoinositide 3-kinases Biochem. J. 2000, 350, 353-359
8. Leslie, N. R.; Downes, C. P. PTEN function: how normal cells control it and tumor cells lose it Biochem. J. 2004, 382, 1-11 (Pubitemid 39141560)
9. Chalhoub, N.; Baker, S. J. PTEN and the PI3-kinase pathway in cancer Annu. Rev. Pathol. 2009, 4, 127-150
10. Hollander, M. C.; Blumenthal, G. M.; Dennis, P. A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models Nat. Rev. Cancer 2011, 11, 289-301
11. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Willson, J. K. V.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency of mutations of the PIK3CA gene in human cancers Science 2004, 304, 554 (Pubitemid 38541907)
12. Campbell, I. G.; Russell, S. E.; Choong, D. Y. H.; Montgomery, K. G.; Ciavarella, M. L.; Hooi, C. S. F.; Cristiano, B. E.; Pearson, R. B.; Phillips, W. A. Mutation of the PIK3CA gene in ovarian and breast cancer Cancer Res. 2004, 64, 7678-7681 (Pubitemid 39446895)
13. Bader, A. G.; Kang, S.; Vogt, P. K. Cancer-specific mutations in PIK3CA are oncogenic in vivo Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 1475-1479 (Pubitemid 43191190)
14. Isakoff, S. J.; Engelman, J. A.; Irie, H. Y.; Luo, J.; Brachmann, S. M.; Pearline, R. V.; Cantley, L. C.; Brugge, J. S. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells Cancer Res. 2005, 65, 10992-11000 (Pubitemid 41713369)
15. Samuels, Y.; Diaz, L. A.; Schmidt-Kittler, O.; Cummins, J. M.; DeLong, L.; Cheong, I.; Rago, C.; Huso, D. L.; Lengauer, C.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutant PIK3CA promotes cell growth and invasion of human cancer cells Cancer Cell 2005, 7, 561-573 (Pubitemid 40799249)
16. Marone, R.; Cmiljanovic, V.; Giese, B.; Wymann, M. P. Targeting phosphoinositide 3-kinase-moving towards therapy Biochim. Biophys. Acta, Proteins Proteomics 2008, 1784, 159-185
17. Shuttleworth, S.; Silva, F.; Tomassi, C.; Cecil, A.; Hill, T.; Rogers, H.; Townsend, P. Progress in the design and development of phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of chronic diseases Prog. Med. Chem. 2009, 48, 81-131
18. Workman, P.; Clarke, P. A.; Raynaud, F. I.; van Montfort, R. L. Drugging the PI3 kinome: from chemical tools to drugs in the clinic Cancer Res. 2010, 70, 2146-2157
19. Shuttleworth, S. J; Silva, F. A.; Cecil, A. R. L.; Tomassi, C. D.; Hill, T. J.; Raynaud, F. I.; Clarke, P. A.; Workman., P. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors Curr. Med. Chem. 2011, 18, 2686-2714
20. Maira, S.-M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol. Cancer Ther. 2008, 7, 1851-1863
21. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J. A.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1 H -indazol-4-yl)-6-(4- methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2- d ]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer J. Med. Chem. 2008, 51, 5522-5532
22. Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.; Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish, C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.; Sung, C.-M.; Sutton, D.; Tummino, P. J.; Wegrzyn, R. J.; Auger, K. R.; Dhanak, D. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin ACS Med. Chem. Lett. 2010, 1, 39-43
23. Cheng, H.; Bagrodia, S.; Bailey, S.; Edwards, M.; Hoffman, J.; Hu, Q.; Kania, R.; Knighton, D. R.; Marx, M. A.; Ninkovic, S.; Sunb, S.; Zhang, E. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design Med. Chem. Commun. 2010, 1, 139-144
24. Lannutti, B. J.; Meadows, S. A.; Herman, S. E. M.; Kashishian, A.; Steiner, B.; Johnson, A. J.; Byrd, J. C.; Tyner, J. W.; Loriaux, M. M.; Deininger, M.; Druker, B. J.; Puri, K. D.; Ulrich, R. G.; Giese, N. A. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability Blood 2011, 117, 591-594
25. Yaguchi, S.; Fukui, Y.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.; Gouda, H.; Hirono, S.; Yamazaki, K.; Yamori, T. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor J. Natl. Cancer Inst. 2006, 98, 545-556 (Pubitemid 43898818)
26. Kong, D.; Yamori, T. ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms Cancer Sci. 2007, 98, 1638-1642 (Pubitemid 47308463)
27. Kong, D.; Yaguchi, S.; Yamori, T. Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase Biol. Pharm. Bull. 2009, 32, 297-300
28. Kong, D.; Yamori, T. ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system Acta Pharmacol. Sin. 2010, 31, 1189-1197
29. Dan, S.; Yoshimi, H.; Okamura, M.; Mukai, Y.; Yamori, T. Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest Biochem. Biophys. Res. Commun. 2009, 379, 104-109
30. Kong, D.; Okamura, M.; Yoshimi, H.; Yamori, T. Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor Eur. J. Cancer 2009, 45, 857-865
31. http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid= 9195752.
32. Sugama, T.; Ishihara, N.; Tanaka, Y.; Takahashi, M.; Yaguchi, S.; Watanabe, T. Amorphous Form of Heterocyclic Compound, Solid Dispersion and Medicinal Preparation Each Comprising the Same, and Process for Production of the Same. PCT Int. Appl. WO 09066775, 2009
33. Chem. Abstr. 2009, 150, 572414.
34. Berndt, A.; Miller, S.; Williams, O.; Le, D. D.; Houseman, B. T.; Pacold, J. I.; Gorrec, F.; Hon, W.; Liu, Y.; Rommel, C.; Gaillard, P; Rückle, T.; Schwarz, M. K.; Shokat, K. M.; Shaw, J. P.; Williams, R. L. The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors Nat. Chem. Biol. 2010, 6, 117-124
35. Zask, A.; Verheijen, J. C.; Richard, D. J.; Kaplan, J.; Curran, K.; Toral-Barza, L.; Lucas, J.; Hollander, I.; Yu, K. Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 2644-2647
36. Matsuno, T.; Kato, M.; Sasahara, H.; Watanabe, T.; Inaba, M.; Takahashi, M.; Yaguchi, S.; Yoshioka, K.; Sakato, M.; Kawashima, S. Synthesis and antitumor activity of benzimidazolyl-1,3,5-triazine and benzimidazolylpyrimidine derivatives Chem. Pharm. Bull. 2000, 48, 1778-1781
37. Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J. One-pot synthesis of 2-trifluoromethyl and 2-difluoromethyl substituted benzo-1,3-diazoles Tetrahedron Lett. 2007, 48, 3251-3254 (Pubitemid 46527749)
38. Dong, C. M.; Chen, L. G.; Duan, X. M.; Shu, X. G.; Zeng, T.; Yan, X. L. 2,4-Dichloro-6-morpholino-1,3,5-triazine Acta Crystallogr. 2005, E61, o1168-o1169
39. Kawashima, S.; Matsuno, T.; Yaguchi, S.; Sasahara, H.; Watanabe, T. Preparation of Heterocyclic Compounds as Antitumor Agents. PCT Int. Appl. WO 02088112, 2002
40. Chem. Abstr. 2002, 137, 370113.
41. Pearlman, W. M.; Banks, C. K. Substituted chlorodiamino- s -triazines J. Am. Chem. Soc. 1948, 70, 3726-3728
42. Barraclough, P.; Black, J. W.; Cambridge, D.; Collard, D.; Firmin, D.; Gerskowitch, V. P.; Glen, R. C.; Giles, H.; Hill, A. P.; Hull, R. A. D.; Iyer, R.; King, W. R.; Kneen, C. O.; Lindon, J. C.; Nobbs, M. S.; Randall, P.; Shah, G. P.; Smith, S.; Vine, S. J.; Whiting, M. V.; Williams, J. M. Inotropic "A" ring substituted sulmazole and isomazole analogs J. Med. Chem. 1990, 33, 2231-2239 (Pubitemid 20236672)
43. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine Mol. Cell 2000, 6, 909-919
44. Camps, M.; Ruckle, T.; Hong, J.; Ardissone, V.; Rintelen, F.; Shaw, J.; Ferrandi, C.; Chabert, C.; Gillieron, C.; Francon, B.; Martin, T.; Gretener, D.; Perrin, D.; Leroy, D.; Vitte, P.-A.; Hirsch, E.; Wymann, M. P.; Cirillo, R.; Schwarz, M. K.; Rommel, C. Blockade of PI3K? suppresses joint inflammation and damage in mouse models of rheumatoid arthritis Nat. Med. 2005, 11, 936-943 (Pubitemid 41294438)
45. Knight, Z. A.; Gonzalez, B.; Feldman, M. E.; Zunder, E. R.; Goldenberg, D. D.; Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.; Toth, B.; Balla, T.; Weiss, W. A.; Williams, R. L.; Shokat, K. M. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling Cell 2006, 125, 733-747
46. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking J. Mol. Biol. 1997, 267, 727-748 (Pubitemid 27170693)
47. SYBYL, version 7.3; Tripos Inc. (1699 South Hanley Road, St. Louis, MO 63144, U.S.).
48. Huang, C.-H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V. E.; Kinzler, K. W.; Vogelstein, B.; Gabelli, S. B.; Amzel, L. M. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations Science 2007, 318, 1744-1748 (Pubitemid 350274378)
49. Haruta, K.; Yaguchi, S.; Matsuno, T.; Tsuchida, Y.; Watanabe, T.; Yoshioka, K.; Yui, R. Immunosuppressive Agent and Anti-Tumor Agent Comprising Heterocyclic Compound as Active Ingredient. PCT Int. Appl. WO 06095906, 2006
50. Chem. Abstr. 2006, 145, 328368.
51. Yaguchi, S.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.; Watanabe, T.; Tsuchida, Y.; Saitoh, K. Treatment of Prostate Cancer, Melanoma or Hepatic Cancer. U.S. Pat. Appl. Publ. 20070244110, 2007
52. Chem. Abstr. 2007, 147, 440304.
53. Kawashima, S.; Matsuno, T.; Yaguchi, S.; Tsuchida, Y.; Saitoh, K.; Watanabe, T. Preparation of 2-Benzimidazolyl-4,6-dimorpholinylpyrimidine and 2-Benzimidazolyl-4,6-dimorpholinyltriazine Derivatives as Antitumor Agents. PCT Int. Appl. WO 05095389, 2005
54. Chem. Abstr. 2005, 143, 367324.
55. Chaussade, C.; Rewcastle, G. W.; Kendall, J. D.; Denny, W. A.; Cho, K. H. Y.; GrØnning, L. M.; Chong, M. L.; Anagnostou, S. H.; Jackson, S. P.; Daniele, N.; Shepherd, P. R. Evidence for functional redundancy of class IA PI3K isoforms in insulin signaling Biochem. J. 2007, 404, 449-458 (Pubitemid 46953919)
56. Jamieson, S.; Flanagan, J. U.; Kolekar, S.; Buchanan, C.; Kendall, J. D.; Lee, W.-J.; Rewcastle, G. W.; Denny, W. A.; Singh, R.; Dickson, J.; Baguley, B. C.; Shepherd, P. R. A drug targeting only p110 α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types Biochem. J. 2011, 438, 53-62
57. Smith, W. T., Jr.; Steinle, E. C., Jr. Some substituted benzimidazoles J. Am. Chem. Soc. 1953, 75, 1292-1294
58. O'Shaughnessy, J.; Aldabbagh, F. Synthesis of pyrrolo- and pyrido[1,2-a]benzimidazolequinone anti-tumor agents containing a fused cyclopropane ring Synthesis 2005, 1069-1076 (Pubitemid 40675997)
59. Sekikawa, I. Antitubercular compounds. XIII. Preparation of some derivatives of benzimidazole and 2,1,3-benzothiadazole Bull. Chem. Soc. Jpn. 1958, 31, 252-254
60. Zhang, L.; Fan, J.; Vu, K.; Hong, K.; Le Brazidec, J.-Y.; Shi, J.; Biamonte, M.; Busch, D. J.; Lough, R. E.; Grecko, R.; Ran, Y.; Sensintaffar, J. L.; Kamal, A.; Lundgren, K.; Burrows, F. J.; Mansfield, R.; Timony, G. A.; Ulm, E. H.; Kasibhatla, S. R.; Boehm, M. F. 7′-Substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors J. Med. Chem. 2006, 49, 5352-5362 (Pubitemid 44260229)
61. Butterworth, S.; Griffen, E. J.; Pass, M. Preparation of Pyrimidine Derivatives Having Inhibitory Activity against PI3K Enzymes. PCT Int. Appl. WO 2008032064, 2008
62. Chem. Abstr. 2008, 148, 355815.
63. Oku, T.; Kawai, Y.; Yatabe, T.; Sato, S.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K. Preparation of Benzimidazoles for the Prevention and/or the Treatment of Bone Diseases. PCT Int. Appl. WO 9710219, 1997
64. Chem. Abstr. 1997, 126, 293352.
65. Boulton, A. J.; Ghosh, P. B.; Katritzky, A. R. Heterocyclic rearrangements. V. Rearrangement of 4-arylazo- and 4-nitrosobenzofuroxans new syntheses of the benzotriazole and benzofurazan ring systems J. Chem. Soc. B 1966, 1004-1011
66. Jones, T. G. H.; Robinson, R. Experiments on the orientation of substituted catechol ethers J. Chem. Soc. Trans. 1917, 111, 903-929
67. Palmer, B. D.; Kraker, A. J.; Hartl, B. G.; Panopoulos, A. D.; Panek, R. L.; Batley, B. L.; Lu, G. H.; Trumpp-Kallmeyer, S.; Showalter, H. D. H.; Denny, W. A. Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as selective inhibitors of the platelet-derived growth factor receptor J. Med. Chem. 1999, 42, 2373-2382 (Pubitemid 29305171)
68. Davies, W. Substitution in vicinal trisubstituted benzene derivatives. I J. Chem. Soc. Trans. 1923, 123, 1575-1593
69. Sommer, K.; Williams, R. M. Studies on paraherquamide biosynthesis: synthesis of deuterium-labeled 7-hydroxy-pre-paraherquamide, a putative precursor of paraherquamides A, E, and F Tetrahedron 2009, 65, 3246-3260
70. Raiford, L. C; Port, W. S.; Perry, R. P. Some derivatives of benzylvanillin and benzylvanillic acid J. Am. Chem. Soc. 1949, 71, 3851
71. Roblot, F.; Hocquemiller, R.; Cave, A. Alkaloids from Annonaceae. 93. First synthesis of a meta-disubstituted aporphine Bull. Soc. Chim. Fr. 1990, 127, 258-267
72. Horner, L.; Schwenk, U.; Junghanns, E. Derivatives of quinoxaline as isosteres of the pteridines Liebigs Ann. Chem. 1953, 579, 212-234
73. Butterworth, S.; Griffen, E. J.; Hill, G. B.; Pass, M. Pyrimidine Derivatives as Antiproliferative Agents and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Diseases. PCT Int. Appl. WO 2008032027, 2008
74. Chem. Abstr. 2008, 148, 379652
75. Chen, V. B.; Arendall, W. B., III; Headd, J. J.; Keedy, D. A.; Immormino, R. M.; Kapral, G. J.; Murray, L. W.; Richardson, J. S.; Richardson, D. C. MolProbity: all-atom structure validation for macromolecular crystallography Acta Crystallogr. 2010, D66, 12-21
76. Powell, M. J. D. Restart procedures for the conjugate gradient method Math Programming 1977, 12, 241-254
77. Kendall, J. D.; Rewcastle, G. W.; Frederick, R.; Mawson, C.; Denny, W. A.; Marshall, E. S.; Baguley, B. C.; Chaussade, C. M.; Jackson, S. P.; Shepherd, P. R. Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110α inhibitors Bioorg. Med. Chem. 2007, 15, 7677-7687 (Pubitemid 47575920)
78. Baguley, B. C.; Marshall, E. S.; Whittaker, J. R.; Dotchin, M. C.; Nixon, J.; McCrystal, M. R.; Finlay, G. J.; Matthews, J. H. L.; Holdaway, K. M.; van Zijl, P. Resistance mechanisms determining the in vitro sensitivity to paclitaxel of tumor cells cultured from patients with ovarian cancer Eur. J. Cancer 1995, 31A, 230-237