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Selective Targeting of Antiapoptotic BCL-2 Proteins in Cancer

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Selective Targeting of Antiapoptotic BCL-2 Proteins in Cancer Received: 21 July 2017 Revised: 5 May 2018 Accepted: 12 May 2018 DOI: 10.1002/med.21516 REVIEW ARTICLE Selective targeting of antiapoptotic BCL-2 proteins in cancer Ahmet Can Timucin1,2 Huveyda Basaga2 Ozgur Kutuk3 1Faculty of Engineering and Natural Sciences, Department of Chemical and Biological Engineering, Uskudar University, Uskudar, Istanbul, Turkey 2Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey 3Department of Medical Genetics, Adana Medical and Research Center, School of Medicine, Baskent University, Yuregir, Adana, Turkey Correspondence Ahmet Can Timucin, Faculty of Engineering and Abstract Natural Sciences, Department of Chemical and Circumvention of apoptotic machinery is one of the distinctive prop- Biological Engineering, Uskudar University, erties of carcinogenesis. Extensively established key effectors of Altunizade Mahallesi, Haluk Turksoy Sk. No:14, 34662 Uskudar, Istanbul, Turkey. such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apop- Email: [email protected]/ can- tosis regulator BCL-2) proteins, determine the response of cancer [email protected] cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, mile- stone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were dis- cussed. In the first section, the design and development of BCL- 2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summa- rized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; BAK, BCL-2 homologous antago- nist/killer; BAX, apoptosis regulator BAX; BCL-2, apoptosis regulator BCL-2; BCL-W, Bcl-2-like protein 2; BCL-XL, BCL-2-like protein 1; BFL-1, BCL-2-related protein A1; BH, BCL-2 homology; BID, BH3-interacting domain death agonist; BIM, BCL-2-like protein 11; CLL, chronic lymphocytic leukemia; CR, complete response; ERK, mitogen-activated protein kinase 3; ETP, early T-cell progenitor; MCL-1, induced myeloid leukemia cell differentiation protein MCL-1; MEF, mouse embryonic fibroblast; MIM1, MCL-1 inhibitor molecule 1; miRNA, microRNA; MULE, MCL-1 ubiquitin ligase E3; NHL, non-Hodgkin lymphoma; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; OS, overall survival; PARP, poly (ADP-ribose) polymerase; PDX, patient-derived xenograft;PR,partial response; PUMA, BCL-2-binding component 3; SCLC, Small cell lung cancer; T-ALL, T-cell acute lymphoblastic leukemia; TRAIL, tumor necrosis factor ligand superfamily member 10; VEGF, vascular endothelial growth factor; wt, wild type Med Res Rev 2018;1–30. wileyonlinelibrary.com/journal/med c 2018 Wiley Periodicals, Inc. 1 2 TIMUCIN ET AL. nonselective and selective targeting of MCL-1, and recently initi- ated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increas- ing selectivity in the design of prosurvival BCL-2 member inhibitors. KEYWORDS antiapoptotic BCL-2 proteins, cancer, small molecules, targeted therapy 1 INTRODUCTION There are primarily two widely established pathways that can lead to apoptosis: (a) extrinsic pathway and (b) intrin- sic pathway.1 The extrinsic pathway is triggered by interaction of an extracellular ligand and tumor necrosis factor receptor family related transmembrane death receptor.2,3 Following this interaction, an adapter binds to the recep- tor, and this binding leads to procaspase-8 activation via death-inducing signaling complex.4,5 Active caspase-8 fur- ther initiates caspase-3, which executes apoptosis.1 Intrinsic pathway, on the other hand, occupies the modifications of the inner mitochondrial membrane.1 These alterations then lead to the opening of mitochondrial transition pore via decreased mitochondrial transmembrane potential and results in the release of proapoptotic proteins to cytoplasm such as cytochrome c.6 As a widely accepted hallmark of the intrinsic apoptotic pathway, cytochrome c interacts with Apaf-1 (apoptotic protease-activating factor 1) and procaspase-9, forming the apoptosome.7 Apoptosome activates procaspase-9, which leads to executioner caspase-3 activation.1 Intrinsic and extrinsic apoptotic pathways are strictly controlled by BCL-2 (apoptosis regulator BCL-2) proteins.8 The founding member of the BCL-2 protein family, BCL-2, was discovered as a part of t(14;18) chromosomal translo- cation in follicular lymphoma and diffuse large B-cell lymphoma.9,10 Currently, more than 20 members of the BCL-2 protein family have been identified based on BCL-2 homology (BH) regions. BCL-2, BCL-XL (BCL-2-like protein 1), MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1), BCL-W (Bcl-2-like protein 2), BFL-1 (BCL-2- related protein A1), and BCL-B (Bcl-2-like protein 10) comprise the antiapoptotic BCL-2 proteins, contain all four BH domains, and inhibit apoptosis by sequestering multidomain prodeath BCL-2 proteins—BAX (apoptosis regulator BAX) and BAK (BCL-2 homologous antagonist/killer)—or by repressing activator BH3-only proteins—BIM (BCL-2-like pro- tein 11), BID (BH3-interacting domain death agonist), PUMA (BCL-2-binding component 3), and NOXA (phorbol-12- myristate-13-acetate-induced protein 1) (Figure 1). Activator BH3-only proteins activate pore-forming effector BAX and BAK proteins via direct protein–protein interaction, which results in their conformational change and oligomeriza- tion on the outer mitochondrial membrane.11–14 Besides, preferential activation of BAX by BIM and BAK by BID has been demonstrated.15 Among these BH3-only proteins, NOXA emerges as a distinct member due to its restricted binding partners, MCL-1 and BFL-1 compared with BIM and BID, which have the capability of targeting all prosurvival BCL-2 members.16,17 Specifically, NOXA-based targeting of MCL-1 results in sequestration of MCL-1 avoiding its interaction with other BH3-only members.18 In turn, NOXA–MCL-1 interaction reduces the half-life of MCL-1 via NOXA-dependent delivery to ubiquitination system and degradation, for instance via E3 ubiquitin ligase MULE (MCL-1 ubiquitin ligase E3).17–21 Overall, the selectivity of NOXA toward MCL-1 may seem to generate a weaker capacity for cell death induction by NOXA. However, this condition could also be translated into increased selectivity when designing specific MCL-1 inhibitors based on NOXA peptide sequence and structure, notably in the setting of cancer.18 The complex network of interactions regulated by the family of BCL-2 proteins guided researchers to use this sys- tem as a preparatory step for efficient cell death in cancer cells. This step, first termed by Certo et al. as “primed for death,” primes the cancer cells initially by death signals so that antiapoptotic BCL-2 proteins get occupied with TIMUCIN ET AL. 3 FIGURE 1 Protein–protein interactions between proapoptotic and antiapoptotic BCL-2 family proteins dictate mitochondrial apoptotic response following cellular stress including DNA damage, oxidative stress, growth factor withdrawal, and metabolic stress. Activator BH3-only proteins (BID, BIM, PUMA, NOXA) directly bind and activate BAX and BAK, which in turn form multimeric pores in the mitochondrial membrane. Antiapoptotic BCL-2 proteins sequester activator BH3-only proteins. Upon cellular damage, sensitizer BH3-only proteins bind to antiapoptotic BCL- 2 proteins to displace activators, which are then free to bind and activate BAK and BAX. Mitochondrial outer mem- brane permeabilization and the translocation of proapoptotic factors such as cytochrome c into cytosol trigger intrinsic apoptotic pathway BH3-only proapoptotic BCL-2 proteins (Figure 2A).22 Through changing the number of available BH3-binding sites on antiapoptotic proteins BCL-2 proteins, a secondary signal via proapoptotic stimuli and BH3 mimetics become a stronger inducer of cell death as compared to their effects alone on an unprimed cell (Figure 2A). In particular, the final phase of the mitochondrial priming involves the direct or indirect activation of pore-forming effectors BAX and BAK via activator BH3-only proapoptotic proteins (Figure 2B). Although mitochondrial priming remains as a powerful tool for overcoming the resistance of antiapoptotic BCL-2 proteins, a clear distinction should be made for identify- ing the specific antiapoptotic BCL-2, which mediates the resistance phenotype. The solution to this problem could be accomplished by a novel method called BH3 profiling.23 Briefly, BH3 peptides with known concentrations are fed to mitochondria, and a measure of mitochondrial permeabilization could reveal the antiapoptotic BCL-2 protein, used for survival purposes. After such a BH3 profiling based
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