Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

Cell Death and Disease

Volumn 6, Issue 1, 2015, Pages

  Leverson, J D ^a   Zhang, H ^a   Chen, J ^a   Tahir, S K ^a   Phillips, D C ^a   Xue, J ^a   Nimmer, P ^a   Jin, S ^a   Smith, M ^a   Xiao, Y ^a   Kovar, P ^a   Tanaka, A ^a,c   Bruncko, M ^a   Sheppard, G S ^a   Wang, L ^a   Gierke, S ^b   Kategaya, L ^b   Anderson, D J ^b,d   Wong, C ^b,e   Eastham Anderson, J ^b   Ludlam, Mj C ^b,f   Sampath, D ^b   Fairbrother, W J ^b   Wertz, I ^b   Rosenberg, S H ^a   Tse, C ^a   Elmore, S W ^a   Souers, A J ^a   more..

^a ABBVIE INC   (United States)

^b GENENTECH INC   (United States)

^c OSAKA UNIVERSITY   (Japan)

^d Cleave Biosciences   (United States)

^e CytomX Therapeutics Inc   (United States)

^f Cairn Biosciences Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 INDOLECARBOXYLIC ACID; A 1210477; ANTINEOPLASTIC AGENT; BH3 PROTEIN; BIM PROTEIN; BORTEZOMIB; MESSENGER RNA; NAVITOCLAX; PROTEIN BAD; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN MCL 1; PROTEIN NOXA; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; ANILINE DERIVATIVE; APOPTOSIS REGULATORY PROTEIN; BCL-2-LIKE PROTEIN 11; INDOLE DERIVATIVE; INDOLE-2-CARBOXYLIC ACID; MEMBRANE PROTEIN; MOLECULAR LIBRARY; ONCOPROTEIN; SULFONAMIDE;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; BINDING AFFINITY; CANCER CELL; CANCER CELL LINE; CELL ACTIVITY; CELL KILLING; CELL PROLIFERATION; CELL SURFACE; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG POTENCY; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG SYNTHESIS; FEMALE; FLUORESCENCE RESONANCE ENERGY TRANSFER; HELA CELL LINE; HUMAN; HUMAN CELL; IC50; MITOCHONDRIAL MEMBRANE; MULTIPLE MYELOMA CELL LINE; NON SMALL CELL LUNG CANCER; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; TARGET CELL; UBIQUITINATION; ANTAGONISTS AND INHIBITORS; CELL SURVIVAL; DRUG EFFECTS; METABOLISM; MOLECULAR LIBRARY; NEOPLASM; PATHOLOGY; PHARMACOLOGY; TUMOR CELL LINE;

ANILINE COMPOUNDS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CELL LINE, TUMOR; CELL SURVIVAL; DRUG SYNERGISM; HUMANS; INDOLES; MEMBRANE PROTEINS; MYELOID CELL LEUKEMIA SEQUENCE 1 PROTEIN; NEOPLASMS; PROTO-ONCOGENE PROTEINS; SMALL MOLECULE LIBRARIES; SULFONAMIDES;

EID: 84924697369     PISSN: None     EISSN: 20414889     Source Type: Journal    
DOI: 10.1038/cddis.2014.561     Document Type: Article

References (70)

1. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell 2010; 37: 299-310.
2. Chi X, Kale J, Leber B, Andrews DW. Regulating cell death at, on, and in membranes. Biochim Biophys Acta 2014; 1843: 2100-2113.
3. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15: 49-63.
4. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9: 351-365.
5. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature 2005; 435: 677-681.
6. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68: 3421-3428.
7. Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D et al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res 2008; 14: 3268-3277.
8. Ackler S, Mitten MJ, Foster K, Oleksijew A, Refici M, Tahir SK et al. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother Pharmacol 2010; 66: 869-880.
9. Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ 2007; 14: 943-951.
10. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
11. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves anti-tumor activity while sparing platelets. Nat Med 2013; 19: 202-208.
12. Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM et al. Structure-guided design of a selective BCL-XL inhibitor. Nat Chem Biol 2013; 9: 390-397.
13. Sleebs BE, Kersten WJ, Kulasegaram S, Nikolakopoulos G, Hatzis E, Moss RM et al. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. J Med Chem 2013; 56: 5514-5540.
14. Koehler MF, Bergeron P, Choo EF, Lau K, Ndubaku C, Dudley D et al. Structure-guided rescaffolding of selective antagonists of BCL-XL. ACS Med Chem Lett 2014; 5: 662-667.
15. Tao Z-F, Hasvold L, Wang L, Wang X, Petros AM, Park CH et al. Discovery of a potent and selective BCL-XL inhibitor that demonstrates on target in vivo activity. ACS Med Chem Lett 2014; 5: 1088-1093.
16. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375-388.
17. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/ Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389-399.
18. Chen S, Dai Y, Harada H, Dent P, Grant S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 2007; 67: 782-791.
19. Tahir SK, Yang X, Anderson MG, Morgan-Lappe SE, Sarthy AV,Warner RB et al. Influence of Bcl-2 family members on SCLC sensitivity to Bcl-2 antagonists. Cancer Res 2007; 67: 1176-1183.
20. Wei SH, Dong K, Lin F, Wang X, Li B, Shen JJ et al. Inducing apoptosis and enhancing chemosensitivity to gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell. Cancer Chemother Pharmacol 2008; 62: 1055-1064.
21. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 2011; 471: 110-114.
22. Akagi H, Higuchi H, Sumimoto H, Igarashi T, Kabashima A, Mizuguchi H et al. Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. Gastric Cancer 2013; 16: 100-110.
23. Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol 2013; 23: 22-29.
24. Beroukhim R, Mermel CH, Porter D,Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899-905.
25. Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival of human myeloma cells. Blood 2002; 100: 194-199.
26. Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 2002; 99: 1885-1893.
27. Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev 2012; 26: 120-125.
28. Song L, Coppola D, Livingston S, Cress D, Haura EB. Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol Ther 2005; 4: 267-276.
29. Zhang H, Guttikonda S, Roberts L, Uziel T, Semizarov D, Elmore SW et al. Mcl-1 is critical for survival in a subgroup of non-small cell lung cancer cell lines. Oncogene 2011; 30: 1963-1968.
30. Kelly GL, Grabow S, Glaser SP, Fitzsimmons L, Aubrey BJ, Okamoto T et al. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev 2014; 28: 58-70.
31. Stewart ML, Fire E, Keating AE, Walensky LD. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol 2010; 6: 595-601.
32. Placzek WJ, Sturlese M, Wu B, Cellitti JF, Wei J, Pellecchia M. Identification of a novel Mcl-1 protein binding motif. J Biol Chem 2011; 286: 39829-39835.
33. Muppidi A, Doi K, Edwardraja S, Drake EJ, Gulick AM, Wang HG et al. Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors. J Am Chem Soc 2012; 134: 14734-14737.
34. Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD. Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem 2013; 14: 1564-1572.
35. Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B et al. A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 2012; 19: 1175-1186.
36. Doi K, Li R, Sung S-S, Wu H, Liu Y, Manieri W et al. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem 2012; 287: 10224-10235.
37. Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS et al. A novel small-molecule inhibitor of MCL-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 2014; 13: 565-575.
38. Friberg A, Vigil D, Zhao B, Daniels RN, Burke JP, Garcia-Barrantes PM et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J Med Chem 2013; 56: 15-30.
39. Richard DJ, Lena R, Bannister T, Blake N, Pierceall WE, Carlson NE et al. Hydroxyquinolinederived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker. Bioorgan Med Chem 2013; 21: 6642-6649.
40. Gojo I, Zhang B, Fenton RG. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of MCL-1. Clin Cancer Res 2002; 8: 3527-3538.
41. MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A et al. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibiton of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res 2005; 65: 5399-5407.
42. Xie G, Tang H, Wu S, Chen J, Liu J, Liao C. The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol 2014; 45: 804-812.
43. Wei G, Margolin AA, Haerin L, Brown E, Cucolo L, Julian B et al. Chemical genomics identifies small-molecule MCL-1 repressors and BCL-xL as a predictor of MCL-1 dependency. Cancer Cell 2012; 21: 547-562.
44. Bruncko M, Wang L, Sheppard G, Petros A, Zhang H, Nimmer P et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J Med Chem 2014 (in press).
45. Mei Y, Du W, Yang Y, Wu M. Puma∗Mcl-1 interaction is not sufficient to prevent repaid degradation of Mcl-1. Oncogene 2005; 24: 7224-7237.
46. Czabotar PE, Lee EF, van Delft ME, Day CL, Smith BJ, Huang DCS. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA 2007; 104: 6217-6222.
47. Hsu YT, Youle RJ. Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem 1997; 272: 13829-13834.
48. Wong C, Anderson DJ, Lee EF, Fairlie WD, Ludlam MJ. Direct visualization of Bcl-2 family protein interactions using live cell fluorescent protein redistribution assays. Cell Death Dis 2012; 3: e288.
49. Lee EF, Czabotar PE, van Delft MF, Michalak EM, Boyle MJ, Willis SN et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol 2008; 180: 341-355.
50. Del Gaizo Moore V, Letai A. BH3 profiling-measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett 2013; 332: 202-205.
51. Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 2008; 11: 2300-2309.
52. Lin X, Morgan-Lappe S, Huang X, Li L, Zakula DM, Vernetti LA et al. 'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small molecule Bcl-2/Bcl-xL inhibitor ABT-737. Oncogene 2007; 26: 3972-3979.
53. Bernardo PH, Sivaraman T, Wan KF, Xu J, Krishnamoorthy J, Song CM et al. Structural insights into the design of small molecule inhibitors that selectively antagonize Mcl-1. J Med Chem 2010; 53: 2314-2318.
54. Petros AM, Swann SL, Song D, Swinger K, Park C, Zhang H et al. Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein. Bioorg Med Chem Lett 2014; 24: 1484-1488.
55. Albershardt TC, Salerni BL, Soderquist RS, Bates DJ, Pletnev AA, Kisselev AF et al. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 2011; 286: 24882-24895.
56. Eichhorn JM, Alford SE, Hughes CC, Fenical W, Chambers TC. Purported MCL-1 inhibitor marinopyrrole A fails to show selective cytotoxicity for MCL-1-dependent cell lines. Cell Death Dis 2013; 4: e880.
57. Varadarajan S, Butterworth M, Wei J, Pellecchia M, Dinsdale D, Cohen GM. Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis. Neoplasia 2013; 15: 568-578.
58. Varadarajan S, Vogler M, Butterworth M, Dinsdale D, Walensky LD, Cohen GM. Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ 2013; 20: 1475-1484.
59. Workman P, Collins I. Probing the probes: fitness factors for small molecule tools. Chem Biol 2010; 17: 561-577.
60. Prueksaritanont T, DeLuna P, Gorham LM, Ma B, Cohn D, Pang J et al. In vitro and in vivo evaluations of intestinal barriers for the zwitterion L-767,679 and its carboxyl ester prodrug L-775,318. Roles of efflux and metabolism. Drug Metab Dispos 26: 520-527.
61. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic Mcl-1. Nature 2003; 426: 671-676.
62. Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K et al. Obligate role of anti-apoptoticMcl-1 in the survival of hematopoietic stemcells. Science 2005; 307: 1101-1104.
63. Dzhagalov I, St. John A, He YW. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 2007; 109: 1620-1626.
64. Vick B, Weber A, Urbanik T, Maass T, Teufel A, Krammer PH et al. Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology 2009; 49: 627-636.
65. Hikita H, Takehara T, Shimizu S, Kodama T, Li W, Miyagi T et al. Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. Hepatology 2009; 50: 1217-1226.
66. Hikita H, Takehara T, Shimizou S, Kodama T, Shigekawa M, Iwase K et al. The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 2010; 52: 1310-1321.
67. Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev 2013; 27: 1351-1364.
68. Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev 2013; 27: 1365-1377.
69. Perciavalle RM, Stewart DP, Koss B, Lynch J, Milasta S, Bathina M et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 2012; 14: 575-583.
70. Xiang Z, Luo H, Payton JE, Cain J, Ley TJ, Opferman JT et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest 2010; 120: 2109-2118.