The discovery of polo-like kinase 4 inhibitors: Identification of (1 R,2 S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1 H -indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent

Journal of Medicinal Chemistry

Volumn 58, Issue 1, 2015, Pages 147-169

  Sampson, Peter B ^a   Liu, Yong ^a   Forrest, Bryan ^a   Cumming, Graham ^b   Li, Sze Wan ^a   Patel, Narendra Kumar ^a   Edwards, Louise ^a   Laufer, Radoslaw ^a   Feher, Miklos ^a   Ban, Fuqiang ^a   Awrey, Donald E ^a   Mao, Guodong ^a   Plotnikova, Olga ^a   Hodgson, Richard ^a   Beletskaya, Irina ^a   Mason, Jacqueline M ^a   Luo, Xunyi ^a   Nadeem, Vincent ^a   Wei, Xin ^a   Kiarash, Reza ^a   Madeira, Brian ^a   Huang, Ping ^a   Mak, Tak W ^a   Pan, Guohua ^a   Pauls, Henry W ^a   more..

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b Celtic Catalysts   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

2 (3 ((E) 4 (((CIS) 2,6 DIMETHYLMORPHOLINO)METHYL)STYRYL) 1H INDAZOL 6 YL) 5' METHOXYSPIRO[CYCLOPROPANE 1,3' INDOLIN] 2' ONE; 2 (3 (4 CIS 2,6 DIMETHYLMORPHOLINO)METHYL)STYRYL) 1H INDAZOL 6 YL) 5' METHOXYSPIRO[CYCLOPROPANE 1,3' INDOLIN] 2' ONE FUMARATE; 2 (3 (4 CIS 2,6 DIMETHYLMORPHOLINO)METHYL)STYRYL) 1H INDAZOL 6 YL) SPIRO[CYCLOPROPANE 1,3' INDOLIN] 2' ONE HYDROCHLORIDE; 5' METHOXY 1' METHYL 2 (3 (4 (MORPHOLINOMETHYL) STYRYL) 1H INDAZOL 6 YL)SPIRO [CYCLOPROPANE 1,3' INDOLIN] 2' ONE HYDROCHLORIDE; ANTINEOPLASTIC AGENT; FLUOROURACIL; POLO LIKE KINASE INHIBITOR; UNCLASSIFIED DRUG; 2-(3-(4-((2,6-DIMETHYLMORPHOLINO)METHYL)STYRYL)-1H-INDAZOL-6-YL)-5'-METHOXYSPIRO(CYCLOPROPANE-1,3'-INDOLIN)-2'-ONE; INDAZOLE DERIVATIVE; INDOLE DERIVATIVE; INDOLIN-2-ONE; PLK4 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE;

AMINO ACID SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BREAST CANCER CELL LINE; CANCER INHIBITION; CANCER THERAPY; CELL ACTIVITY; CELL DEATH; CONTROLLED STUDY; DIASTEREOISOMER; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG EXPOSURE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SYNTHESIS; ENANTIOMER; ENANTIOSELECTIVITY; HUMAN; HUMAN CELL; MAXIMUM TOLERATED DOSE; MCF 7 CELL LINE; NONHUMAN; RAT; STEREOCHEMISTRY; STEREOISOMERISM; TUMOR VOLUME; ANIMAL; BIOAVAILABILITY; CELL SURVIVAL; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; DOG; DRUG DEVELOPMENT; DRUG EFFECTS; DRUG SCREENING; FEMALE; HCT116 CELL LINE; MALE; METABOLISM; NEOPLASMS; NUDE MOUSE; ORAL DRUG ADMINISTRATION; PATHOLOGY; SCID MOUSE; STRUCTURE ACTIVITY RELATION; TUMOR CELL LINE;

ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; CELL SURVIVAL; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FEMALE; HCT116 CELLS; HUMANS; INDAZOLES; INDOLES; MALE; MCF-7 CELLS; MICE, NUDE; MICE, SCID; MODELS, CHEMICAL; MOLECULAR STRUCTURE; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84920814085     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5005336     Document Type: Article

References (49)

1. Barr, F. A.; Silljé, H. H. W.; Nigg, E. A. Polo-like kinases and the orchestration of cell division Nature Rev. Mod. Cell. Biol. 2004, 5, 429-440
2. Archambault, V.; Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation Nature Rev. Mol. Cell Biol. 2009, 10, 265-275
3. Schoffski, P. Polo-like kinase inhibitors in preclinical and early clinical development Oncologist 2009, 14, 559-570
4. Sillibourne, J. E.; Bornens, M. Polo-like kinase 4: the odd one out of the family Cell Div. 2010, 5, 25-34
5. Bettencourt-Dias, M.; Rodrigues-Martins, A.; Carpenter, L.; Riparbelli, M.; Lehmenn, L.; Gatt, M. K.; Carmo, N.; Balloux, F.; Callani, G.; Glover, D. M. SAK/PLK4 is required for centriole duplication and flagella development Curr. Biol. 2005, 15, 2199-2207
6. Habedanck, R.; Stierhof, Y.-D.; Wilkinson, C. J.; Nigg, E. A. The Polo kinase PLK4 functions in centriole duplication Nature. Cell Biol. 2005, 7, 1140-1146
7. Kleylein-Sohn, J.; Westendorf, J.; Le Clech, M.; Habedanck, R.; Stierhof, Y.-D.; Nigg, E. A. Plk4-induced centriole biogenesis in human cells Dev. Cell 2007, 13, 190-202
8. Ko, M. A.; Rosario, C. O.; Hudson, J. W.; Kulkarni, S.; Pollett, A.; Dennis, J. W.; Swallow, C. J. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis Nature Genet. 2005, 37, 883-888
9. Basto, R.; Brunk, K.; Vinadogrova, T.; Peel, N.; Franz, A.; Khodjakov, A.; Raff, J. W. Centrosome amplification can initiate tumorigenesis in flies Cell 2008, 133, 1032-1042
10. Liu, L.; Zhang, C. Z.; Cai, M.; Fu, J.; Chen, G. G.; Yun, J. Downregulation of polo-like kinase 4 in hepatocellular carcinoma associates with poor prognosis PLoS One 2012, 7, e41293
11. Hu, Z.; Fan, C.; Oh, D. S.; Marron, J. S.; He, X.; Qaqish, B. F.; Livasy, C.; Carey, L. A.; Reynolds, E.; Dressler, L.; Nobel, A.; Parker, J.; Ewend, M. G.; Sawyer, L. R.; Wu, J.; Liu, Y.; Nanda, R.; Tretiakova, M.; Orrico, A. R.; Dreher, D.; Palazzo, J. P.; Perreard, L.; Nelson, E.; Mone, M.; Hansen, H.; Mullins, M.; Quackenbush, J. F.; Ellis, M. J.; Olopade, O. I.; Bernard, P. S.; Perou, C. M. The molecular portraits of breast tumors are conserved across microarray platforms BMC Genomics 2006, 7, 96-108
12. van di Vijver, M. J.; He, Y. D.; van t Veer, L.; Dai, H.; Hart, A. A. M.; Voskuil, D. W.; Schreiber, G. J.; Peterse, J. L.; Roberts, C.; Marton, M. J.; Parrish, M.; Atsma, D.; Witteveen, A.; Glas, A.; Delahaye, L.; van der Velde, T.; Bartelink, H.; Rodenhuis, S.; Rutgers, E. T.; Friend, S. H.; Bernards, R. A gene-expression signature as a predictor of survival in breast cancer N. Engl. J. Med. 2002, 347, 1999-2009
13. Miller, L. D.; Smeds, J.; George, J.; Vega, V. B.; Vergara, L.; Ploner, A.; Pawitan, Y.; Hall, P.; Klaar, S.; Liu, E. T.; Bergh, J. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 13550-13555
14. Mason, J.; Wei, S.; Luo, S.; Nadeem, V.; Kiarash, R.; Huang, P.; Awrey, A.; Leung, G.; Beletskaya, I.; Feher, M.; Forrest, B.; Laufer, R.; Sampson, P.; Li, S.-W.; Liu, Y.; Lang, Y.; Pauls, H. W.; Mak, T. W.; Pan, J. G. Inhibition of Polo-like kinase 4 as an anti-cancer strategy. AACR 102nd Annual Meeting, Orlando, FL, April 2-6, 2011, LB-215.
15. Mak, T. W. Targeting the Cell Cycle in Cancer: TTK (MPS1) and PLK4 as Novel Mitotic Targets. AACR 103rd Annual Meeting, Chicago, IL, April 1-5, 2012.
16. Pauls, H. W. PLK4 inhibitors of novel structure as potent anti-proliferative agents. 241st ACS National Meeting, Anaheim, CA, March 27-31, 2011, MEDI 189.
17. Laufer, R.; Forrest, B.; Li, S.-W.; Sampson, P.; Liu, Y.; Edwards, L.; Lang, Y.; Awrey, D.; Mao, V.; Plotnikova, O.; Leung, G.; Hodgson, R.; Beletskaya, I.; Mason, J.; Wei, S.; Luo, X.; Nadeem, V.; Feher, M.; Kiarash, R.; Green, E.; Mak, T. W.; Pan, J. G.; Pauls, H. W. The discovery of PLK4 inhibitors: (E)-3-((1 H -indazol-6-yl)methylene)indolin-2-ones as novel anti-proliferative agents J. Med. Chem. 2013, 56, 6069-6087
18. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.; Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. A quantitative analysis of kinase inhibitor selectivity Nature Biotechnol. 2008, 26, 127-132
19. Sebolt-Leopold, J. S.; English, J. M. Mechanisms of drug inhibition of signalling molecules Nature 2006, 441, 457-462
20. Bain, J.; McLauchlan, H.; Elliott, M.; Cohen, P. The specificities of protein kinase inhibitors: an update Biochem. J. 2003, 371, 199-204
21. Knight, Z. A.; Shokat, K. M. Features of selective kinase inhibitors Chem. Biol. 2005, 12, 621-637
22. McInnes, C.; Mezna, M.; Fischer, P. M. Progress in the discovery of polo-like kinase inhibitors Curr. Top. Med. Chem. 2005, 5, 181-197
23. Reindl, W.; Yuan, J.; Kramer, A.; Strebhardt, K.; Berg, T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions Chem. Biol. 2008, 15, 459-466
24. Sampson, P. B.; Liu, Y.; Patel, N. K.; Feher, M.; Forrest, B.; Li, S.-W.; Edwards, L.; Laufer, R.; Lang, Y.; Ban, F.; Awrey, D.; Mao, G.; Plotnikova, O.; Leung, G.; Hodgson, R.; Mason, J.; Wei, X.; Kiarash, R.; Green, E.; Qiu, W.; Chirgadze, N. Y.; Mak, T. W.; Pan, G.; Pauls, H. W. The discovery of PLK4 inhibitors: design and optimization of spiro[cyclopropane-1,3′[3 H ]indol]-2′(1′ H)-ones as anti-cancer agents. J. Med. Chem. DOI 10.1021/jm500537u.
25. Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Asymmetric ylide reactions: epoxidation, cyclo-propanation, aziridination, olefination, and rearrangement Chem. Rev. 1997, 97, 2341-2372
26. Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Application of chiral sulfides to catalytic asymmetric aziridination and cyclopropanation with in situ generation of the diazo compound Angew. Chem., Int. Ed. 2001, 40, 1433-1436
27. Marti, C.; Carreira, E. M. Total synthesis of (-)-spirotryprostatin B: synthesis and related studies J. Am. Chem. Soc. 2005, 127, 11505-11515
28. Yun, G.; Sharpless, K. B. Vicinal diol cyclic sulfates. Like epoxides only more reactive J. Am. Chem. Soc. 1988, 110, 7538-7539
29. Pauls, H. W. The discovery of PLK4 inhibitors as novel anti-proliferative agents. Canadian Chemistry Conference & Exhibition, Quebec City, QC, May 26-29, 2013, BM7-00029.
30. Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. An efficient method for the N -debenzylation of aromatic heterocycles Tetrahedron Lett. 2002, 43, 399-402
31. Williams, R. M.; Kwast, E. Carbanion-mediated oxidative deprotection of non-enolizable benzylated amides Tetrahedron Lett. 1989, 30, 451-454
32. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Catalytic assymmetric dihydroxylation Chem. Rev. 1994, 94, 2483-2547
33. Hunter, C. A.; Sanders, J. K. M. The nature of π-π interactions J. Am. Chem. Soc. 1990, 112, 5525-5534
34. Bhosale, S. S.; Joshi, P. L.; Rae, A. S. A convenient procedure for the preparation of 2-bromo-1-phenylethanol Org. Prep. Proced. Int. 2009, 24, 695-696
35. Weinstock, J.; Ladd, D. L.; Wilson, J. W.; Brush, C. K.; Yim, N.C. F.; Gallagher, G., Jr.; McCarthy, M. E.; Silvestri, J.; Sarau, H. M.; Flaim, K. E.; Ackerman, D. M.; Setler, P. E.; Tobia, A. J.; Hahns, R. A. Synthesis and renal vasodilator activity of some dopamine agonist l-aryl-2,3,4,5-tetrahydro-1 H -3-benzazepine-7,8-diols: halogen and methyl analogues of fenoldopam J. Med. Chem. 1986, 29, 2315-2325
36. Smolinsky, G. Formation of azacyclopropenes by pyrolysis of vinyl azides J. Org. Chem. 1962, 27, 3557-3559
37. Manfredi, M. G.; Ecsedy, J. A.; Meetze, K. A.; Balani, S. K.; Burenkova, O.; Chen, W.; Galvin, K. M.; Hoar, K. M.; Huck, J. J.; LeRoy, P. J.; Ray, E. T.; Sells, T. B.; Stringer, B.; Stroud, S. G.; Vos, T. J.; Weatherhead, G. S.; Wysong, D. R.; Zhang, M.; Bolen, J. B.; Claiborne, C. F. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 4106-4111
38. Innocenti, P.; Cheung, K-M.J.; Solanki, S.; Mas-Droux, C.; Rowan, F.; Yeoh, S.; Boxall, K.; Westlake, M.; Pickard, L.; Hardy, T.; Baxter, J. E.; Aherne, G. W.; Bayliss, R.; Fry, A. M.; Hoelder, S. Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: SAR, structural biology and cellular activity J. Med. Chem. 2012, 55, 3228-3241
39. Mason, J. M.; Lin, D.C-C.; Wei, X.; Che, Y.; Yao, Y.; Kiarash, R.; Fletcher, G. C.; Bray, M. R.; Pan, G. J.; Mak, T. W. Inhibition of PLK4 as a therapeutic strategy for genomically unstable cancers deficient for PTEN. AACR-NCI-EORTC International Conference on Molecular Targets & Cancer Therapeutics, Boston, MA, October 19-23, 2013, B267.
40. Mason, J. M.; Lin, D.C-C.; Wei, X.; Che, Y.; Yao, Y.; Kiarash, R.; Cescon, D. W.; Fletcher, G. C.; Awrey, D. E.; Bray, M. R.; Pan, G.; Mak, T. W. Functional characterization of CFI-400945, an inhibitor of PLK4, as a potential anticancer agent. Cancer Cell 2014, in press
41. ACD/Structure Designer, version 12.01; Advanced Chemistry Development, Inc.: Toronto, ON, Canada, 2012.
42. Nakagawara, A.; Azar, C. G.; Scavarda, N. J.; Brodeur, G. M. Expression and function of TRK-B and BDNF in human neuroblastomas Mol. Cell. Biol. 1994, 14, 759-767
43. Peters, K. G.; Coogan, A.; Berry, D.; Marks, J.; Iglehart, J. D.; Kontos, C. D.; Rao, P.; Sankar, S.; Trogan, E. Expression of Tie2/Tek in breast tumor vasculature provides a new marker for evaluation of tumour angiogenesis Br. J. Cancer 1998, 77, 51-56
44. Fister, R.; Panetta, J. C. Optimal control applied to cell-cycle-specific cancer chemotherapy SIAM J. Appl. Math. 2000, 60, 1059-1072
45. Venugopal, B.; Baird, R.; Kristeleit, R. S.; Plummer, R.; Cowan, R.; Stewart, A.; Fourneau, N.; Hellemans, P.; Elsayed, Y.; Mcclue, S.; Smit, J. W.; Forslund, A.; Phelps, C.; Camm, J.; Evans, T. R. J.; de Bono, J. S.; Banerji, U. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors Clin. Cancer Res. 2013, 19, 4262-4272
46. Wei, P.; Walls, M.; Qiu, M.; Ding, R.; Denlinger, R. H.; Wong, A.; Tsaparikos, K.; Jani, J. P.; Hosea, N.; Sands, M.; Randolph, S.; Smeal, T. Evaluation of selective γ-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design Mol. Cancer Ther. 2010, 9, 1618-1628
47. Awar, O.; Duvic, M. Treatment of transformed mycosis fungoides with intermittent low-dose Gemcitabine Oncology 2007, 73, 130-135
48. MOE (Molecular Operating Environment), version 2005.06; Chemical Computing Group Inc.: 1010 Sherbrooke St. West, Suite 910, Montreal, Quebec, H3A 2R7, Canada, 2005.
49. Usansky, J. I.; Desai, A.; Tang-Liu, D. PK Functions for Microsoft Excel. Pharmacokinetic Software; David W. A. Bourne, 2001-2003; http://www.boomer.org/pkin/soft.html, Accessed November, 2008.