Table Info

Table 3.

Select clinical trials of Mcl-1-specific inhibitors

Mcl-1 inhibitor	Clinical trial number	Phase	Intervention	Disease	Status
MIK665 (S64315)	NCT02992483	I	MIK665 (S64315)	MM, DLBCL, and lymphoma	Completed
MIK665 (S64315)	NCT04702425	I	MIK665 in combination with Bcl-2 inhibitor VOB560	NHL, AML, and MM	Ongoing
MIK665 (S64315)	NCT04629443	I/II	S64315 plus azacitidine	AML	Ongoing
MIK665 (S64315)	NCT02979366	I	S64315	AML and MDS	Completed
S64315	NCT03672695	I	S64315 plus venetoclax	AML	Ongoing
Gossypol (AT-101)	NCT00390403	I	AT-101 plus temozolomide with or without radiation therapy	Glioblastoma multiforme	Completed
AMG176	NCT02675452	I	AMG176, azacitidine, itraconazole	Relapsed or refractory MM and AML	Ongoing
AMG397	NCT03465540	I	AMG397, azacitidine, dexamethasone	MM, AML, NHL, and MDS	Terminated

DLBCL: diffuse large B-cell lymphoma; MDS: myelodysplastic syndrome. Source: clinicaltrials.gov

Declarations

Acknowledgment

All the figures were created using the BioRender.com application.

Author contributions

PS reviewed the literature and prepared the manuscript draft. Both authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors have no potential or existing conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Meier P, Finch A, Evan G. Apoptosis in development. Nature. 2000;407:796–801. [DOI] [PubMed]

Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:770–6. [DOI] [PubMed]

Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419. [DOI] [PubMed]

Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2008;18:157–64. [DOI] [PubMed] [PMC]

Michels J, Johnson PW, Packham G. Mcl-1. Int J Biochem Cell Biol. 2005;37:267–71. [DOI] [PubMed]

Craig RW, Jabs EW, Zhou P, Kozopas KM, Hawkins AL, Rochelle JM, et al. Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease. Genomics. 1994;23:457–63. [DOI] [PubMed]

Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci U S A. 1993;90:3516–20. [DOI] [PubMed] [PMC]

Thomas LW, Lam C, Edwards SW. Mcl-1; the molecular regulation of protein function. FEBS Lett. 2010;584:2981–9. [DOI] [PubMed]

Opferman JT. Unraveling MCL-1 degradation. Cell Death Differ. 2006;13:1260–2. [DOI] [PubMed]

10.

Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev. 2000;14:23–7. [DOI] [PubMed] [PMC]

11.

Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K, et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science. 2005;307:1101–4. [DOI] [PubMed]

12.

Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2009;66:1326–36. [DOI] [PubMed]

13.

Sieghart W, Losert D, Strommer S, Cejka D, Schmid K, Rasoul-Rockenschaub S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol. 2006;44:151–7. [DOI] [PubMed]

14.

Song L, Coppola D, Livingston S, Cress WD, Haura EB. Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol Ther. 2005;4:267–76. [DOI] [PubMed]

15.

Mallick S, Patil R, Gyanchandani R, Pawar S, Palve V, Kannan S, et al. Human oral cancers have altered expression of Bcl-2 family members and increased expression of the anti-apoptotic splice variant of Mcl-1. J Pathol. 2009;217:398–407. [DOI] [PubMed]

16.

Gong JN, Khong T, Segal D, Yao Y, Riffkin CD, Garnier JM, et al. Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016;128:1834–44. [DOI] [PubMed]

17.

Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9:5341. [DOI] [PubMed] [PMC]

18.

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;26:120–5. [DOI] [PubMed] [PMC]

19.

Placzek WJ, Wei J, Kitada S, Zhai D, Reed JC, Pellecchia M. A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy. Cell death Dis. 2010;1:e40. [DOI] [PubMed] [PMC]

20.

Ertel F, Nguyen M, Roulston A, Shore GC. Programming cancer cells for high expression levels of Mcl1. EMBO Rep. 2013;14:328–36. [DOI] [PubMed] [PMC]

21.

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. [DOI] [PubMed] [PMC]

22.

Sheng Z, Li L, Zhu LJ, Smith TW, Demers A, Ross AH, et al. A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med. 2010;16:671–7. [DOI] [PubMed] [PMC]

23.

Malin S, McManus S, Cobaleda C, Novatchkova M, Delogu A, Bouillet P, et al. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nat Immunol. 2010;11:171–9. [DOI] [PubMed] [PMC]

24.

Allen JC, Talab F, Zuzel M, Lin K, Slupsky JR. c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells. Blood. 2011;117:2414–22. [DOI] [PubMed]

25.

Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, et al. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci U S A. 2008;105:10853–8. [DOI] [PubMed] [PMC]

26.

Mott JL, Kobayashi S, Bronk SF, Gores GJ. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 2007;26:6133–40. [DOI] [PubMed] [PMC]

27.

Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, et al. MicroRNA 29b functions in acute myeloid leukemia. Blood. 2009;114:5331–41. [DOI] [PubMed] [PMC]

28.

Desjobert C, Renalier MH, Bergalet J, Dejean E, Joseph N, Kruczynski A, et al. MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression. Blood. 2011;117:6627–37. [DOI] [PubMed]

29.

Bae J, Leo CP, Hsu SY, Hsueh AJ. MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem. 2000;275:25255–61. [DOI] [PubMed]

30.

Kim JH, Sim SH, Ha HJ, Ko JJ, Lee K, Bae J. MCL-1ES, a novel variant of MCL-1, associates with MCL-1L and induces mitochondrial cell death. FEBS Lett. 2009;583:2758–64. [DOI] [PubMed]

31.

Palve V, Mallick S, Ghaisas G, Kannan S, Teni T. Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers. PloS One. 2014;9:e111927. [DOI] [PubMed] [PMC]

32.

Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005;121:1085–95. [DOI] [PubMed]

33.

Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, et al. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27:4006–17. [DOI] [PubMed] [PMC]

34.

Harley ME, Allan LA, Sanderson HS, Clarke PR. Phosphorylation of Mcl-1 by CDK1–cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 2010;29:2407–20. [DOI] [PubMed] [PMC]

35.

Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, et al. SCF (FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471:104–9. [DOI] [PubMed] [PMC]

36.

Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–7. [DOI] [PubMed]

37.

Sulkshane P, Pawar SN, Waghole R, Pawar SS, Rajput P, Uthale A, et al. Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers. Br J Cancer. 2021;125:547–60. [DOI] [PubMed]

38.

Morgan EL, Patterson MR, Barba-Moreno D, Scarth JA, Wilson A, Macdonald A. The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer. Oncogene. 2021;40:2112–29. [DOI] [PubMed] [PMC]

39.

Yang P, Xie J, Li Y, Lin HP, Fenske W, Clementino M, et al. Deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and benzo(a)pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis. Theranostics. 2020;10:9050–65. [DOI] [PubMed] [PMC]

40.

Nakano T, Go T, Nakashima N, Liu D, Yokomise H. Overexpression of antiapoptotic MCL-1 predicts worse overall survival of patients with non-small cell lung cancer. Anticancer Res. 2020;40:1007–14. [DOI] [PubMed]

41.

Pepper C, Lin TT, Pratt G, Hewamana S, Brennan P, Hiller L, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008;112:3807–17. [DOI] [PubMed]

42.

Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, et al. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis. 2018;9:19. [DOI] [PubMed] [PMC]

43.

Shigemasa K, Katoh O, Shiroyama Y, Mihara S, Mukai K, Nagai N, et al. Increased MCL-1 expression is associated with poor prognosis in ovarian carcinomas. Jpn J Cancer Res. 2002;93:542–50. [DOI] [PubMed] [PMC]

44.

Li XX, Zhou JD, Wen XM, Zhang TJ, Wu DH, Deng ZQ, et al. Increased MCL-1 expression predicts poor prognosis and disease recurrence in acute myeloid leukemia. Onco Targets Ther. 2019;12:3295–304. [DOI] [PubMed] [PMC]

45.

Wen Q, Zhan Y, Zheng H, Zang H, Luo J, Zhang Y, et al. Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer. Diagn Pathol. 2019;14:108. [DOI] [PubMed] [PMC]

46.

Zhang T, Zhao C, Luo L, Zhao H, Cheng J, Xu F. The expression of Mcl-1 in human cervical cancer and its clinical significance. Med Oncol. 2012;29:1985–91. [DOI] [PubMed]

47.

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;16:100–10. [DOI] [PubMed]

48.

Reiner T, de Las Pozas A, Parrondo R, Palenzuela D, Cayuso W, Rai P, et al. Mcl-1 protects prostate cancer cells from cell death mediated by chemotherapy-induced DNA damage. Oncoscience. 2015;2:703–15. [DOI] [PubMed] [PMC]

49.

Schulze-Bergkamen H, Fleischer B, Schuchmann M, Weber A, Weinmann A, Krammer PH, et al. Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction. BMC Cancer. 2006;6:232. [DOI] [PubMed] [PMC]

50.

Michels J, Obrist F, Vitale I, Lissa D, Garcia P, Behnam-Motlagh P, et al. MCL-1 dependency of cisplatin-resistant cancer cells. Biochem Pharmacol. 2014;92:55–61. [DOI] [PubMed]

51.

Yu X, Li W, Xia Z, Xie L, Ma X, Liang Q, et al. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis. BMC Cancer. 2017;17:449. [DOI] [PubMed] [PMC]

52.

Ma J, Zhao Z, Wu K, Xu Z, Liu K. MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC. Gene. 2016;587:147–54. [DOI] [PubMed]

53.

Guoan X, Hanning W, Kaiyun C, Hao L. Adenovirus-mediated siRNA targeting Mcl-1 gene increases radiosensitivity of pancreatic carcinoma cells in vitro and in vivo. Surgery. 2010;147:553–61. [DOI] [PubMed]

54.

Trivigno D, Essmann F, Huber SM, Rudner J. Deubiquitinase USP9x confers radioresistance through stabilization of Mcl-1. Neoplasia. 2012;14:893–904. [DOI] [PubMed] [PMC]

55.

Skvara H, Thallinger C, Wacheck V, Monia BP, Pehamberger H, Jansen B, et al. Mcl-1 blocks radiation-induced apoptosis and inhibits clonogenic cell death. Anticancer Res. 2005;25:2697–703. [PubMed]

56.

Palve VC, Teni TR. Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells. Radiat Oncol. 2012;7:135. [DOI] [PubMed] [PMC]

57.

Sulkshane P, Teni T. BH3 mimetic obatoclax (GX15-070) mediates mitochondrial stress predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells. Oncotarget. 2016;8:60060–79. [DOI] [PubMed] [PMC]

58.

Wood KC. Overcoming MCL-1-driven adaptive resistance to targeted therapies. Nat Commun. 2020;11:531. [DOI] [PubMed] [PMC]

59.

Montero J, Gstalder C, Kim DJ, Sadowicz D, Miles W, Manos M, et al. Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies. Nat Commun. 2019;10:5157. [DOI] [PubMed] [PMC]

60.

Gomez-Bougie P, Ménoret E, Juin P, Dousset C, Pellat-Deceunynck C, Amiot M. Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction. Biochem Biophys Res Commun. 2011;413:460–4. [DOI] [PubMed]

61.

Sale MJ, Minihane E, Monks NR, Gilley R, Richards FM, Schifferli KP, et al. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Nat Commun. 2019;10:5167. [DOI] [PubMed] [PMC]

62.

Shi P, Oh YT, Deng L, Zhang G, Qian G, Zhang S, et al. Overcoming acquired resistance to AZD9291, a third-generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation. Clin Cancer Res. 2017;23:6567–79. [DOI] [PubMed] [PMC]

63.

Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017;36:787–96. [DOI] [PubMed] [PMC]

64.

Song X, Shen L, Tong J, Kuang C, Zeng S, Schoen RE, et al. Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer. Theranostics. 2020;10:8098–110. [DOI] [PubMed] [PMC]

65.

Kasper S, Breitenbuecher F, Heidel F, Hoffarth S, Markova B, Schuler M, et al. Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies. Blood Cancer J. 2012;2:e60. [DOI] [PubMed] [PMC]

66.

He K, Chen D, Ruan H, Li X, Tong J, Xu X, et al. BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells. Oncotarget. 2016;7:47699–710. [DOI] [PubMed] [PMC]

67.

Fofaria NM, Frederick DT, Sullivan RJ, Flaherty KT, Srivastava SK. Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. Oncotarget. 2015;6:40535–56. [DOI] [PubMed] [PMC]

68.

Young AI, Law AM, Castillo L, Chong S, Cullen HD, Koehler M, et al. MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. Breast Cancer Res. 2016;18:125. [DOI] [PubMed] [PMC]

69.

Zhang L, Ming L, Yu J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat. 2007;10:207–17. [DOI] [PubMed] [PMC]

70.

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;10:389–99. [DOI] [PubMed] [PMC]

71.

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;68:3421–8. [DOI] [PubMed]

72.

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;10:375–88. [DOI] [PubMed]

73.

Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010;115:3304–13. [DOI] [PubMed] [PMC]

74.

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;67:782–91. [DOI] [PubMed]

75.

Hormi M, Birsen R, Belhadj M, Huynh T, Cantero Aguilar L, Grignano E, et al. Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML. Eur J Haematol. 2020;105:588–96. [DOI] [PubMed]

76.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82. [DOI] [PubMed]

77.

Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res. 2008;14:1649–57. [DOI] [PubMed]

78.

Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal. 2011;5:101–10. [DOI] [PubMed] [PMC]

79.

Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33. [DOI] [PubMed] [PMC]

80.

McConkey DJ, Zhu K. Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist Updat. 2008;11:164–79. [DOI] [PubMed]

81.

Lü S, Wang J. The resistance mechanisms of proteasome inhibitor bortezomib. Biomark Res. 2013;1:13. [DOI] [PubMed] [PMC]

82.

Nencioni A, Hua F, Dillon CP, Yokoo R, Scheiermann C, Cardone MH, et al. Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis. Blood. 2005;105:3255–62. [DOI] [PubMed]

83.

Zhou W, Hu J, Tang H, Wang D, Huang X, He C, et al. Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors. BMC Cancer. 2011;11:485. [DOI] [PubMed] [PMC]

84.

Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104:19512–7. [DOI] [PubMed] [PMC]

85.

Germain M, Nguyen AP, Le Grand JN, Arbour N, Vanderluit JL, Park DS, et al. MCL-1 is a stress sensor that regulates autophagy in a developmentally regulated manner. EMBO J. 2011;30:395–407. [DOI] [PubMed] [PMC]

86.

Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB, et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 2013;27:1365–77. [DOI] [PubMed] [PMC]

87.

Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, et al. A non-apoptotic function of MCL-1 in promoting pluripotency and modulating mitochondrial dynamics in stem cells. Stem Cell Reports. 2018;10:684–92. [DOI] [PubMed] [PMC]

88.

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;15:568–78. [DOI] [PubMed] [PMC]

89.

Jamil S, Stoica C, Hackett TL, Duronio V. MCL-1 localizes to sites of DNA damage and regulates DNA damage response. Cell Cycle. 2010;9:2843–55. [DOI] [PubMed] [PMC]

90.

Jamil S, Mojtabavi S, Hojabrpour P, Cheah S, Duronio V. An essential role for MCL-1 in ATR-mediated CHK1 phosphorylation. Mol Biol Cell. 2008;19:3212–20. [DOI] [PubMed] [PMC]

91.

Pawlikowska P, Leray I, de Laval B, Guihard S, Kumar R, Rosselli F, et al. ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response. Cell Death Differ. 2010;17:1739–50. [DOI] [PubMed] [PMC]

92.

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;14:575–83. [DOI] [PubMed] [PMC]

93.

Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology. 2005;42:1329–38. [DOI] [PubMed]

94.

Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood. 2005;105:3303–11. [DOI] [PubMed]

95.

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 inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005;65:5399–407. [DOI] [PubMed]

96.

Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005;106:1042–7. [DOI] [PubMed] [PMC]

97.

Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, Seiden MV. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol. 2009;63:681–9. [DOI] [PubMed] [PMC]

98.

Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos AS, et al. Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther. 2006;5:621–9. [DOI] [PubMed]

99.

Thyrell L, Arulampalam V, Hjortsberg L, Farnebo M, Grandér D, Pokrovskaja Tamm K. Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity. Exp Cell Res. 2007;313:4015–24. [DOI] [PubMed]

100.

Nam S, Williams A, Vultur A, List A, Bhalla K, Smith D, et al. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol Cancer Ther. 2007;6:1400–5. [DOI] [PubMed]

101.

Huang M, Dorsey JF, Epling-Burnette PK, Nimmanapalli R, Landowski TH, Mora LB, et al. Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene. 2002;21:8804–16. [DOI] [PubMed]

102.

Mow BM, Chandra J, Svingen PA, Hallgren CG, Weisberg E, Kottke TJ, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002;99:664–71. [DOI] [PubMed]

103.

Thallinger C, Wolschek MF, Maierhofer H, Skvara H, Pehamberger H, Monia BP, et al. Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Clin Cancer Res. 2004;10:4185–91. [DOI] [PubMed]

104.

Wacheck V, Cejka D, Sieghart W, Losert D, Strommer S, Crevenna R, et al. Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells. Cancer Biol Ther. 2006;5:1348–54. [DOI] [PubMed]

105.

Thallinger C, Wolschek MF, Wacheck V, Maierhofer H, Günsberg P, Polterauer P, et al. Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J Invest Dermatol. 2003;120:1081–6. [DOI] [PubMed]

106.

Gao Y, Koide K. Chemical perturbation of Mcl-1 pre-mRNA splicing to induce apoptosis in cancer cells. ACS Chem Biol. 2013;8:895–900. [DOI] [PubMed] [PMC]

107.

Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood. 2011;117:156–64. [DOI] [PubMed] [PMC]

108.

Huber S, Oelsner M, Decker T, Zum Büschenfelde CM, Wagner M, Lutzny G, et al. Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1. Leukemia. 2011;25:838–47. [DOI] [PubMed]

109.

Wang B, Xie M, Li R, Owonikoko TK, Ramalingam SS, Khuri FR, et al. Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. Cell Death Differ. 2014;21:1160–9. [DOI] [PubMed] [PMC]

110.

Villalobos-Ortiz M, Ryan J, Mashaka TN, Opferman JT, Letai A. BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics. Cell Death Differ. 2020;27:999–1007. [DOI] [PubMed] [PMC]

111.

Ryan J, Letai A. BH3 profiling in whole cells by fluorimeter or FACS. Methods. 2013;61:156–64. [DOI] [PubMed] [PMC]

112.

Bhola PD, Ahmed E, Guerriero JL, Sicinska E, Su E, Lavrova E, et al. High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Sci Signal. 2020;13:eaay1451. [DOI] [PubMed] [PMC]

113.

Montero J, Letai A. Dynamic BH3 profiling-poking cancer cells with a stick. Mol Cell Oncol. 2016;3:e1040144. [DOI] [PubMed] [PMC]

114.

Fletcher S. MCL-1 inhibitors–where are we now (2019)? Expert Opin Ther Pat. 2019;29:909–19. [DOI] [PubMed]

115.

Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol Ther. 2019;198:59–67. [DOI] [PubMed]

116.

Mittal P, Singh S, Sinha R, Shrivastava A, Singh A, Singh IK. Myeloid cell leukemia 1 (MCL-1): structural characteristics and application in cancer therapy. Int J Biol Macromol. 2021;187:999–1018. [DOI] [PubMed]

117.

Lee S, Wales TE, Escudero S, Cohen DT, Luccarelli J, Gallagher CG, et al. Allosteric inhibition of antiapoptotic MCL-1. Nat Struct Mol Biol. 2016;23:600–7. [DOI] [PubMed] [PMC]

118.

Li K. Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology. Bioorg Med Chem Lett. 2021;32:127717. [DOI] [PubMed]

119.

Benabderrahmane M, Bureau R, Voisin-Chiret AS, Sopkova-de Oliveira Santos J. Insights into Mcl-1 conformational states and allosteric inhibition mechanism from molecular dynamics simulations, enhanced sampling, and pocket crosstalk analysis. J Chem Inf Model. 2020;60:3172–87. [DOI] [PubMed]

120.

Tanaka Y, Aikawa K, Nishida G, Homma M, Sogabe S, Igaki S, et al. Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins. J Med Chem. 2013;56:9635–45. [DOI] [PubMed]

121.

D de Araujo A, Lim J, Wu KC, Xiang Y, Good AC, Skerlj R, et al. Bicyclic helical peptides as dual inhibitors selective for Bcl2A1 and Mcl-1 proteins. J Med Chem. 2018;61:2962–72. [DOI] [PubMed]

122.

Kump KJ, Miao L, Mady ASA, Ansari NH, Shrestha UK, Yang Y, et al. Discovery and characterization of 2, 5-substituted benzoic acid dual inhibitors of the anti-apoptotic Mcl-1 and Bfl-1 proteins. J Med Chem. 2020;63:2489–510. [DOI] [PubMed] [PMC]

123.

Doi K, Li R, Sung SS, 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;287:10224–35. [DOI] [PubMed] [PMC]

124.

Paiva SL, Crews CM. Targeted protein degradation: elements of PROTAC design. Curr Opin Chem Biol. 2019;50:111–9. [DOI] [PubMed] [PMC]

125.

Wang Z, He N, Guo Z, Niu C, Song T, Guo Y, et al. Proteolysis targeting chimeras for the selective degradation of Mcl-1/Bcl-2 derived from nonselective target binding ligands. J Med Chem. 2019;62:8152–63. [DOI] [PubMed]

126.

Iqbal S, Zhang S, Driss A, Liu ZR, Kim HRC, Wang Y, et al. PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells. PLoS One. 2012;7:e30764. [DOI] [PubMed] [PMC]

127.

Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, et al. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc Natl Acad Sci U S A. 2019;116:2961–6. [DOI] [PubMed] [PMC]

128.

Wu Q, Yang F, Yang Z, Fang Z, Fu W, Chen W, et al. Long noncoding RNA PVT1 inhibits renal cancer cell apoptosis by up-regulating Mcl-1. Oncotarget. 2017;8:101865–75. [DOI] [PubMed] [PMC]

129.

Chen G, Park D, Magis AT, Behera M, Ramalingam SS, Owonikoko TK, et al. Mcl-1 interacts with Akt to promote lung cancer progression. Cancer Res. 2019;79:6126–38. [DOI] [PubMed] [PMC]

130.

Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21. [DOI] [PubMed] [PMC]

131.

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;13:565–75. [DOI] [PubMed] [PMC]

132.

Takahashi H, Chen MC, Pham H, Angst E, King JC, Park J, et al. Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells. Biochim Biophys Acta. 2011;1813:1465–74. [DOI] [PubMed] [PMC]

133.

Mallick S, Agarwal J, Kannan S, Pawar S, Kane S, Teni T. PCNA and anti-apoptotic Mcl-1 proteins predict disease-free survival in oral cancer patients treated with definitive radiotherapy. Oral Oncol. 2010;46:688–93. [DOI] [PubMed]

134.

Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, deBock CE, Thorne RF, et al. Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Res. 2008;68:6708–17. [DOI] [PubMed]

135.

Wuillème-Toumi S, Robillard N, Gomez P, Moreau P, Le Gouill S, Avet-Loiseau H, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia. 2005;19:1248–52. [DOI] [PubMed]

136.

Le Gouill S, Podar K, Amiot M, Hideshima T, Chauhan D, Ishitsuka K, et al. VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood. 2004;104:2886–92. [DOI] [PubMed]

137.

Kaufmann SH, Karp JE, Svingen PA, Krajewski S, Burke PJ, Gore SD, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998;91:991–1000. [DOI] [PubMed]

138.

Michels J, O’Neill JW, Dallman CL, Mouzakiti A, Habens F, Brimmell M, et al. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene. 2004;23:4818–27. [DOI] [PubMed]

139.

Cho-Vega JH, Rassidakis GZ, Admirand JH, Oyarzo M, Ramalingam P, Paraguya A, et al. MCL-1 expression in B-cell non-Hodgkin’s lymphomas. Hum Pathol. 2004;35:1095–100. [DOI] [PubMed]

140.

Li R, Cheng C, Balasis ME, Liu Y, Garner TP, Daniel KG, et al. Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors. Eur J Med Chem. 2015;90:315–31. [DOI] [PubMed] [PMC]