Recent Advances in the Development of Selective Mcl-1 Inhibitors for the Treatment of Cancer (2017-Present)

Ying       Fan; Xuben       Hou; Hao       Fang

doi:10.2174/1574892815666200916124641

Abstract

Background: Myeloid cell leukemia-1 (Mcl-1) protein, as a critical pro-survival member of the B-cell lymphoma 2 (Bcl-2) protein family, plays an important role in apoptosis, carcinogenesis and resistance to chemotherapies. Hence, potently and selectively inhibiting Mcl-1 to induce apoptosis has become a widely accepted anticancer strategy.

Objective: This review intends to provide a comprehensive overview of patents and primary literature, published from 2017 to present, on small molecule Mcl-1 inhibitors with various scaffolds. By analyzing the modes of compound-protein interactions, the similarities and differences of those structures are discussed, which could provide guidance for future drug design.

Methods: The primary accesses for patent searching are SciFinder and Espacenet®. Besides the data disclosed in patents, some results published in the follow-up research papers will be included in this review.

Results: The review covers dozens of patents on Mcl-1 inhibitors in the past three years, and the scaffolds of compounds are mainly divided into indole scaffolds and non-indole scaffolds. The compounds described here are compared with the relevant inhibitors disclosed in previous patents, and representative compounds, especially those launched in clinical trials, are emphasized in this review.

Conclusion: For most of the compounds in these patents, analyses of the binding affinity to Mcl-1 and studies in multiple cell lines were conducted, wherein some compounds were tested in preclinical cancer models or were included in other biological studies. Some compounds showed promising results and potential for further study.

Keywords: Anticancer, apoptosis, drug design, Mcl-1, patent, selective inhibitor.

« Previous Next »

[1] 
Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol  2007; 35(4): 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483] 
[2] 
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(1): 49-63.
[http://dx.doi.org/10.1038/nrm3722] [PMID: 24355989] 
[3] 
Moreira I, Fernandes PA, Ramos MJ. Hot spots-A review of the protein-protein interface determinant amino-acid residues. Proteins: Struct Funct Bioinf  2010; 68(4): 803-12.
[http://dx.doi.org/10.1002/prot.21396] 
[4] 
Hatok J, Racay P. Bcl-2 family proteins: Master regulators of cell survival. Biomol Concepts  2016; 7(4): 259-70.
[http://dx.doi.org/10.1515/bmc-2016-0015] [PMID: 27505095] 
[5] 
Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: The balancing act of Bcl-2 family proteins. Nat Rev Mol Cell Biol  2019; 20(3): 175-93.
[http://dx.doi.org/10.1038/s41580-018-0089-8] [PMID: 30655609] 
[6] 
Adams JM, Cory S. The Bcl-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ  2018; 25(1): 27-36.
[http://dx.doi.org/10.1038/cdd.2017.161] [PMID: 29099483] 
[7] 
Shamas-Din A, Brahmbhatt H, Leber B, Andrews DW. BH3-only proteins: Orchestrators of apoptosis. Biochim Biophys Acta  2011; 1813(4): 508-20.
[http://dx.doi.org/10.1016/j.bbamcr.2010.11.024] [PMID: 21146563] 
[8] 
Ghiotto F, Fais F, Bruno S. BH3-only proteins: The death-puppeteer’s wires. Cytometry A  2010; 77(1): 11-21.
[PMID: 19899133] 
[9] 
Dutta C, Day T, Kopp N, et al. BCL2 suppresses PARP1 function and nonapoptotic cell death. Cancer Res  2012; 72(16): 4193-203.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-4204] [PMID: 22689920] 
[10] 
Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-mimetic drugs: Blazing the trail for new cancer medicines. Cancer Cell  2018; 34(6): 879-91.
[http://dx.doi.org/10.1016/j.ccell.2018.11.004] [PMID: 30537511] 
[11] 
Yamaguchi R, Lartigue L, Perkins G. Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy. Pharmacol Ther  2019; 195: 13-20.
[http://dx.doi.org/10.1016/j.pharmthera.2018.10.009] [PMID: 30347215] 
[12] 
Deng J. How to unleash mitochondrial apoptotic blockades to kill cancers? Acta Pharm Sin B  2017; 7(1): 18-26.
[http://dx.doi.org/10.1016/j.apsb.2016.08.005] [PMID: 28119805] 
[13] 
Kline MP, Rajkumar SV, Timm MM, et al. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia  2007; 21(7): 1549-60.
[http://dx.doi.org/10.1038/sj.leu.2404719] [PMID: 17460700] 
[14] 
Tse C, Shoemaker AR, Adickes J, et al. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res  2008; 68(9): 3421-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5836] [PMID: 18451170] 
[15] 
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med  2013; 19(2): 202-8.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630] 
[16] 
Delbridge AR, Strasser A. The Bcl-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ  2015; 22(7): 1071-80.
[http://dx.doi.org/10.1038/cdd.2015.50] [PMID: 25952548] 
[17] 
Kvansakul M, Hinds MG. The Bcl-2 family: Structures, interactions and targets for drug discovery. Apoptosis  2015; 20(2): 136-50.
[http://dx.doi.org/10.1007/s10495-014-1051-7] [PMID: 25398535] 
[18] 
Jullien M, Gomez-Bougie P, Chiron D, Touzeau C. Restoring apoptosis with BH3 mimetics in mature B-Cell malignancies. Cells  2020; 9(3): E717.
[http://dx.doi.org/10.3390/cells9030717] [PMID: 32183335] 
[19] 
Chao JR, Wang JM, Lee SF, et al. Mcl-1 is an immediate-early gene activated by the Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol  1998; 18(8): 4883-98.
[http://dx.doi.org/10.1128/MCB.18.8.4883] [PMID: 9671497] 
[20] 
Jourdan M, De Vos J, Mechti N, Klein B. Regulation of Bcl -2 -family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ  2000; 7(12): 1244-52.
[http://dx.doi.org/10.1038/sj.cdd.4400758] [PMID: 11175262] 
[21] 
Huelsemann MF, Patz M, Beckmann L, et al. Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia  2015; 29(4): 981-4.
[http://dx.doi.org/10.1038/leu.2014.320] [PMID: 25376373] 
[22] 
Becker TM, Boyd SC, Mijatov B, et al. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene  2014; 33(9): 1158-66.
[http://dx.doi.org/10.1038/onc.2013.45] [PMID: 23455323] 
[23] 
Mojsa B, Lassot I, Desagher S. Mcl-1 ubiquitination: unique regulation of an essential survival protein. Cells  2014; 3(2): 418-37.
[http://dx.doi.org/10.3390/cells3020418] [PMID: 24814761] 
[24] 
Michels J, O’Neill JW, Dallman CL, 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(28): 4818-27.
[http://dx.doi.org/10.1038/sj.onc.1207648] [PMID: 15122313] 
[25] 
Yang-Yen HF. Mcl-1: A highly regulated cell death and survival controller. J Biomed Sci  2006; 13(2): 201-4.
[http://dx.doi.org/10.1007/s11373-005-9064-4] [PMID: 16456709] 
[26] 
Wuillème-Toumi S, Robillard N, Gomez P, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia  2005; 19(7): 1248-52.
[http://dx.doi.org/10.1038/sj.leu.2403784] [PMID: 15902294] 
[27] 
Wei G, Twomey D, Lamb J, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of Mcl-1 and glucocorticoid resistance. Cancer Cell  2006; 10(4): 331-42.
[http://dx.doi.org/10.1016/j.ccr.2006.09.006] [PMID: 17010674] 
[28] 
Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature  2011; 471(7336): 110-4.
[http://dx.doi.org/10.1038/nature09779] [PMID: 21368834] 
[29] 
Bose P, Grant S. Mcl-1 as a therapeutic target in Acute Myelogenous Leukemia (AML). Leuk Res Rep  2013; 2(1): 12-4.
[http://dx.doi.org/10.1016/j.lrr.2012.11.006] [PMID: 23977453] 
[30] 
Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev  2012; 26(2): 120-5.
[http://dx.doi.org/10.1101/gad.182980.111] [PMID: 22279045] 
[31] 
Koss B, Morrison J, Perciavalle RM, et al. Requirement for antiapoptotic Mcl-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood  2013; 122(9): 1587-98.
[http://dx.doi.org/10.1182/blood-2012-06-440230] [PMID: 23881917] 
[32] 
Aichberger KJ, Mayerhofer M, Krauth MT, 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(8): 3303-11.
[http://dx.doi.org/10.1182/blood-2004-02-0749] [PMID: 15626746] 
[33] 
Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood  2002; 100(1): 194-9.
[http://dx.doi.org/10.1182/blood.V100.1.194] [PMID: 12070027] 
[34] 
Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol Ther  2019; 198: 59-67.
[http://dx.doi.org/10.1016/j.pharmthera.2019.02.007] [PMID: 30790641] 
[35] 
Belmar J, Fesik SW. Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther  2015; 145: 76-84.
[http://dx.doi.org/10.1016/j.pharmthera.2014.08.003] [PMID: 25172548] 
[36] 
Denis C, Sopková-de Oliveira Santos J, Bureau R, Voisin-Chiret AS. Hot-Spots of Mcl-1 Protein. J Med Chem  2020; 63(3): 928-43.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00983] [PMID: 31580668] 
[37] 
Chen L, Fletcher S. Mcl-1 inhibitors: A patent review. Expert Opin Ther Pat  2017; 27(2): 163-78.
[http://dx.doi.org/10.1080/13543776.2017.1249848] 
[38] 
Kotschy A, Szlavik Z, Murray J, et al. The Mcl 1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature  2016; 538(7626): 477-82.
[http://dx.doi.org/10.1038/nature19830] [PMID: 27760111] 
[39] 
Letai A. S63845, an Mcl-1 selective BH3 mimetic: Another arrow in our quiver. Cancer Cell  2016; 30(6): 834-5.
[http://dx.doi.org/10.1016/j.ccell.2016.11.016] [PMID: 27960083] 
[40] 
Caenepeel S, Brown SP, Belmontes B, et al. AMG 176, a selective Mcl 1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov  2018; 8(12): 1582-97.
[PMID: 30254093] 
[41] 
Tron AE, Belmonte MA, Adam A, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun  2018; 9(1): 5341.
[http://dx.doi.org/10.1038/s41467-018-07551-w] [PMID: 30559424] 
[42] 
Bruncko M, Wang L, Sheppard GS, et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J Med Chem  2015; 58(5): 2180-94.
[http://dx.doi.org/10.1021/jm501258m] [PMID: 25679114] 
[43] 
Hird A, Belmonte MA, Yang WZ, et al. Macrocyclic Mcl-1 inhibitors for treating cancer.  WO2017182625, 2017.
[44] 
Packer MJ, Perkins DR, Swallow S, et al. Mcl-1 inhibitors and methods of use thereof.  WO2018178226, 2018.
[45] 
Friberg A, Vigil D, Zhao B, 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(1): 15-30.
[http://dx.doi.org/10.1021/jm301448p] [PMID: 23244564] 
[46] 
Burke JP, Bian Z, Shaw S, et al. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J Med Chem  2015; 58(9): 3794-805.
[http://dx.doi.org/10.1021/jm501984f] [PMID: 25844895] 
[47] 
Pelz NF, Bian Z, Zhao B, et al. Discovery of 2-indole-acylsulfonamide Myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods. J Med Chem  2016; 59(5): 2054-66.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01660] [PMID: 26878343] 
[48] 
Lee T, Tarr JC, Jeon K, et al. Substituted indole Mcl-1 inhibitors. WO2017152076, 2017.
[49] 
Ramsey HE, Fischer MA, Lee T, et al.  A novel Mcl1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov  2018; 8(12): 1566-81.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0140] [PMID: 30185627] 
[50] 
Lee T, Christov PP, Shaw S, et al. Discovery of potent Myeloid cell leukemia-1 (Mcl-1) inhibitors that demonstrate in vivo activity in mouse xenograft models of human cancer. J Med Chem  2019; 62(8): 3971-88.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01991] [PMID: 30929420] 
[51] 
Ferrara SJ, Serrano-Wu MH, Lemke C, et al. Macrocyclic fluorine substituted indole derivatives as Mcl-1 inhibitors, for use in the treatment of cancer. WO2019096909, 2019.
[52] 
Szlávik Z, Ondi L, Csékei M, et al. Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity. J Med Chem  2019; 62(15): 6913-24.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00134] [PMID: 31339316] 
[53] 
Kotschy A, Szlávik Z, Csékei M, et al. New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions
containing them. WO2015097123, 2015.
[54] 
Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer  2017; 117(8): 1089-98.
[http://dx.doi.org/10.1038/bjc.2017.281] [PMID: 29017180] 
[55] 
Paczal A, Szlávik Z, Kotschy A, et al. New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them. WO2017125224, 2017.
[56] 
Brown SP, Li YX, Lizarzaburu ME, et al. Tetrahydronaphthalene derivatives that inhibit Mcl-1 protein. WO2016033486, 2016.
[57] 
Yi X, Sarkar A, Kismali G, et al. AMG-176, an Mcl-1 antagonist, shows preclinical efficacy in chronic lymphocytic leukemia. Clin Cancer Res  2020; 26(14): 3856-67.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1397] [PMID: 31937611] 
[58] 
Caenepeel SR, Belmontes B, Sun J, Coxon A, Moody G, Hughes PE. Abstract 2027: Preclinical evaluation of AMG 176, a novel, potent and selective Mcl-1 inhibitor with robust anti-tumor activity in Mcl-1 dependent cancer models. Cancer Res  2017; 77(13): 2027.
[59] 
Brown SP, Bedke DK, Degraffenreid MR, et al. Compounds that inhibit Mcl-1 protein. WO2017147410, 2017.
[60] 
Harrington PE, Ashton K, Brown SP, et al. Compounds that inhibit Mcl-1 protein. WO2018183418, 2018.
[61] 
Brown SP, Lanman BA, Li KX, Li YX, Reed AB. Compounds that inhibit Mcl-1 protein. WO2019036575, 2019.
[62] 
Brown SP, Harrington PE, Lanman BA, et al. Macrocyclic compounds that inhibit Mcl-1 protein. WO2019046150, 2019.
[63] 
Leverson JD, Zhang H, Chen J, et al. 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 Dis  2015; 6: e1590.
[http://dx.doi.org/10.1038/cddis.2014.561] [PMID: 25590800] 
[64] 
Besbes S, Pocard M, Mirshahi M, Billard C. The first Mcl-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia. Crit Rev Oncol Hematol  2016; 100: 32-6.
[http://dx.doi.org/10.1016/j.critrevonc.2016.02.003] [PMID: 26899021] 
[65] 
Brady P, Braje W, Dai YJ, et al. Macrocyclic Mcl-1 inhibitors and methods of use. WO2019035914, 2019.
[66] 
Petros AM, Swann SL, Song D, et al. Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein. Bioorg Med Chem Lett  2014; 24(6): 1484-8.
[http://dx.doi.org/10.1016/j.bmcl.2014.02.010] [PMID: 24582986] 
[67] 
Fletcher S, Lanning M, Chen LJ. Small molecule inhibitors of the Mcl-1 oncoprotein and uses thereof. WO2017011323, 2017.
[68] 
Lanning ME, Yu W, Yap JL, et al. Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein. Eur J Med Chem  2016; 113: 273-92.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.006] [PMID: 26985630] 
[69] 
Chen L, Wilder PT, Drennen B, et al. Structure-based design of 3 -carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1). Org Biomol Chem  2016; 14(24): 5505-10.
[http://dx.doi.org/10.1039/C5OB02063H] [PMID: 26751150] 
[70] 
Fletcher S, Mackerell D. Selective α-cyanoacrylamide and α- cyanoacrylate inhibitors of the Mcl-1 oncoprotein and methods of
using the same. WO2019040467, 2019.
[71] 
Abulwerdi FA, Liao C, Mady AS, et al. 3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: Structure-based design, synthesis, SAR, and biological evaluation. J Med Chem  2014; 57(10): 4111-33.
[http://dx.doi.org/10.1021/jm500010b] [PMID: 24749893] 
[72] 
Nikolovska-Coleska Z, Stuckey JA, Mady A, Miao L. Small molecule inhibitors of Mcl-1 and uses thereof. US9884841 2018.
[73] 
Kump KJ, Miao L, Mady ASA, 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(5): 2489-510.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01442] [PMID: 31971799] 
[74] 
Drennen B, Scheenstra JA, Yap JL, et al. Structural re-engineering of the α-helix mimetic JY-1-106 into small molecules: disruption of the Mcl-1-Bak-BH3 protein-protein interaction with 2,6-di-substituted nicotinates. ChemMedChem  2016; 11(8): 827-33.
[http://dx.doi.org/10.1002/cmdc.201500461] [PMID: 26844930] 
[75] 
Wang A, Song T, Wang Z, et al. Mechanism of Mcl-1 conformational regulation upon small molecule binding revealed by molecular dynamic simulation. Chem Biol Drug Des  2016; 87(4): 551-61.
[http://dx.doi.org/10.1111/cbdd.12679] [PMID: 26518611] 

Rights & Permissions Print Cite

Article Metrics

52

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574892815666200916124641	Print ISSN 1574-8928
Publisher Name Bentham Science Publisher	Online ISSN 2212-3970

Recent Patents on Anti-Cancer Drug Discovery

Recent Advances in the Development of Selective Mcl-1 Inhibitors for the Treatment of Cancer (2017-Present)

Abstract

Related Journals

Related Books

Related Articles