Small Molecule Mcl-1 Inhibitors Research Articles

Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein

Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia.

Abstract A60: Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: Therapeutic implications

Abstract Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here, we demonstrate for the first time strong correlation between Mcl-1 protein levels and hypoxia, predominantly in Her2-positive BC cells. Surprisingly, genetic depletion of Mcl-1 decreased Her2 and Hif-1α levels followed by inhibition of BC cell survival. In contrast, Mcl-1 protein levels were not downregulated after genetic depletion of Her2 indicating a regulatory role of Mcl-1 upstream of Her2. Indeed, Mcl-1 and Her2 co-localize within the mitochondrial fraction and form a Mcl-1/Her2- protein complex. Similar to genetically targeting Mcl-1 the novel small molecule Mcl-1 inhibitor EU-5346 induced cell death and decreased spheroid formation in Her2-positive BC cells. Of interest, EU-5346 induced ubiquitination of Mcl-1- bound Her2 demonstrating a previously unknown role for Mcl-1 to stabilize Her2 protein levels. Importantly, targeting Mcl-1 was also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. In summary, our data demonstrate a critical role of Mcl-1 in Her2-positive BC cell survival under hypoxic conditions and provide the preclinical framework for the therapeutic use of novel Mcl-1- targeting agents to improve patient outcome in BC. Citation Format: Muhammad Hasan Bashari, Fengjuan Fan, Sonia Vallet, M. Arn, Michael H. Cardone, Philipp Beckhove, Andreas Schneeweiss, Martin Sattler, Joseph T. Opferman, Dirk Jäger, Klaus Podar. Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: Therapeutic implications. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A60.

Abstract 3658: Structure-guided de novo design of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization

Abstract Myeloid cell leukemia-1 (Mcl-1) is a potent anti-apoptotic protein, member of the prosurvival Bcl-2 family. Amplification of the gene encoding the Mcl-1 protein is a common genetic aberration in human cancer. Overexpression of Mcl-1 is associated with high tumor grade, resistance to chemotherapy and poor prognosis in many types of cancers. Thus Mcl-1 is emerging as a critical survival factor in a broad range of human cancers and represents an attractive molecular target for development of a new class of cancer therapy. There is still need for developing BH3 mimetics that can efficiently and selectively target Mcl-1 protein. Employing de-novo structure-based drug-design, we have designed a new class of potent small-molecule Mcl-1 inhibitors based on the initial lead compound discovered by high-throughput screening. Analyzing the binding model of this compound with Mcl-1 through computational docking supported by HSQC NMR studies, and using the structural information, we have designed and optimized a class of small-molecule inhibitors of Mcl-1 using a 2-(phenylsulfonamido) benzoic acid as a scaffold to reproduce the key interactions with Mcl-1 such as the conserved hydrogen bond between the aspartate in pro-apoptotic proteins and Arg263 in Mcl-1. Several co-crystal structures of this class inhibitors in complex with Mcl-1 have provided a basis for their further optimization which ultimately led to the discovery of ligands with low-nanomolar potency (Ki = 8 nM) and selectivity for Mcl-1. These compounds bind in the canonical BH3 binding groove. Interestingly, depending on the particular substitution pattern in the core scaffold, a “flip’ binding mode was observed where the substituents bind in a reverse orientation. These findings were confirmed by X-ray crystallography. The most potent compounds were further biologically characterized with a series of complementary biochemical and functional assays. Citation Format: Ahmed Mady, Lei Miao, Andrej Perdih, Chenzhong Liao, Naval Bajwa, Jeanne Stuckey, Zaneta Nikolovska-Coleska. Structure-guided de novo design of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2015-3658

Abstract B76: Targeting Mcl-1 for radiosensitization of pancreatic cancers

Abstract In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and, thus, improve survival in patients with locally advanced pancreatic cancer, we conducted an siRNA library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to gemcitabine-radiation. Thus, we investigated Mcl-1 inhibition by genetic (siRNA) and pharmacological (small molecule) approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA radiosensitized BxPC-3, Panc-1, and MiaPaCa-2 cells with radiation enhancement ratios (RER) of 1.5±0.06, 1.4±0.03, and 1.3±0.01, respectively, and caused Caspase-3 activation and PARP cleavage. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI-77 (Abulwerdi F et al., Mol Cancer Ther, 2014), to inhibit the anti-apoptotic functions of Mcl-1 and radiosensitize in pancreatic cancer cells. Consistent with inhibition of Mcl-1 anti-apoptotic function, UMI-77 (1-5uM) caused dissociation of Mcl-1 from the pro-apoptotic protein Bak. Under these same conditions, UMI-77 produced significant radiosensitization in BxPC-3 and Panc-1 cells (RER: 1.5±0.1 and 1.3±0.04, respectively; P<0.05) with minimal radiosensitization of MiaPaCa-2 cells (1.2±0.07). Since Mcl-1 expression levels are highest in BxPC-3 and Panc-1 cells and lowest in MiaPaCa-2 cells, these results suggest that elevated Mcl-1 protein levels may be a biomarker for radiosensitization by Mcl-1 inhibition. In addition, radiosensitization by UMI-77 was associated with Caspase-3 activation, PARP cleavage, and increased sub-G1 DNA content. In contrast, ABT-737, a well-established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 in radiation survival. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the efficacy of small molecules which displace Mcl-1 from Bak/Bax as radiosensitizers in pancreatic cancer. Furthermore, these results support continued investigation of UMI-77 and its analogues in animal models and in combination with gemcitabine-radiation as a strategy for radiation and chemoradiation sensitization of pancreatic cancers. Citation Format: Qiang Zhang, Dongping Wei, Jason Schreiber, Tasneem Kausar, Theodore Lawrence, Yi Sun, Zaneta Nikolovska-Coleska, Meredith A. Morgan. Targeting Mcl-1 for radiosensitization of pancreatic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B76.

Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.

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).

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells

Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.

Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers.

BackgroundAltered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells.MethodsThe expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed.ResultsAnti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (P<0.02). In oral cancer patients, high Mcl-1L expression was significantly associated with node positivity (P = 0.021), advanced tumor size (P = 0.013) and poor overall survival (P = 0.002). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for oral cancers (P = 0.037). Mcl-1L shRNA knockdown or its inhibition by Obatoclax in combination with Cisplatin synergistically reduced viability and growth of oral cancer cells than either treatment alone.ConclusionOur studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.

408 A potent and selective small molecule inhibitor of MCL-1 sensitizes DLBCL cell lines to the BCL-2 selective inhibitor ABT-199

408 A potent and selective small molecule inhibitor of MCL-1 sensitizes DLBCL cell lines to the BCL-2 selective inhibitor ABT-199

Small molecule Mcl-1 inhibitors for the treatment of cancer.

The Bcl-2 family of proteins serves as primary regulators of apoptosis. Myeloid cell leukemia 1 (Mcl-1), a pro-survival member of the Bcl-2 family of proteins, is overexpressed and the Mcl-1 gene is amplified in many tumor types. Moreover, the overexpression of Mcl-1 is the cause of resistance to several chemotherapeutic agents. Thus, Mcl-1 is a promising cancer target. This review highlights the current progress on the discovery of small molecule Mcl-1 inhibitors.

Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression

Acute myeloid leukemia (AML) is one of the deadliest leukemias for which there is an urgent and unmet need for the development of novel treatment strategies. Multiple drug resistance mechanisms mediate poor drug response and relapse in patients, and a selective Mcl-1 inhibitor has been speculated to be a promising agent in the treatment of AML. Here, we describe that maritoclax, a small molecule Mcl-1 inhibitor, induces Mcl-1 proteasomal degradation without transcriptional downregulation. Maritoclax killed AML cell lines and primary cells with elevated Mcl-1 levels through selective Mcl-1 downregulation, and synergized with ABT-737 to overcome Mcl-1-mediated ABT-737 resistance. Maritoclax was more effective than daunorubicin at inducing leukemic cell death when co-cultured with HS-5 bone marrow stroma cells, while being less toxic than daunorubicin against HS-5 stroma cells, primary mouse bone marrow cells, and hematopoietic progenitor cells. Moreover, maritoclax administration at 20 mg/kg/d intraperitoneally caused significant U937 tumor shrinkage, as well as 36% tumors remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells. In summary, our studies suggest that maritoclax belongs to a novel class of Mcl-1 inhibitors that has the potential to be developed for the treatment of AML.

A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.

Using a high-throughput screening (HTS) approach, we have identified and validated several small-molecule Mcl-1 inhibitors (SMI). Here, we describe a novel selective Mcl-1 SMI inhibitor, 2 (UMI-77), developed by structure-based chemical modifications of the lead compound 1 (UMI-59). We have characterized the binding of UMI-77 to Mcl-1 by using complementary biochemical, biophysical, and computational methods and determined its antitumor activity against a panel of pancreatic cancer cells and an in vivo xenograft model. UMI-77 binds to the BH3-binding groove of Mcl-1 with Ki of 490 nmol/L, showing selectivity over other members of the antiapoptotic Bcl-2 family. UMI-77 inhibits cell growth and induces apoptosis in pancreatic cancer cells in a time- and dose-dependent manner, accompanied by cytochrome c release and caspase-3 activation. Coimmunoprecipitation experiments revealed that UMI-77 blocks the heterodimerization of Mcl-1/Bax and Mcl-1/Bak in cells, thus antagonizing the Mcl-1 function. The Bax/Bak-dependent induction of apoptosis was further confirmed using murine embryonic fibroblasts that are Bax- and Bak-deficient. In an in vivo BxPC-3 xenograft model, UMI-77 effectively inhibited tumor growth. Western blot analysis in tumor remnants revealed enhancement of proapoptotic markers and significant decrease of survivin. Collectively, these promising findings show the therapeutic potential of Mcl-1 inhibitors against pancreatic cancer and warrant further preclinical investigations.

Highlights of This Issue

Poor localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. To overcome these limits, Shin and colleagues designed a novel solid tumor–penetrating antibody format, mAb-A22p, by genetic fusion of high-affinity neuropilin-targeting A22p peptide to the C-terminus of the heavy chain of the conventional mAbs, such as anti-EGFR cetuximab and anti-Her2 trastuzumab. The mAb-A22p antibodies showed much better tumor homing, extravasation from the vessels, and tumor tissue penetration, resulting in more potent antitumor efficacy, compared with the parent mAbs. This study indicates that mAb-A22p is a superior format for solid tumor–targeting therapeutic antibodies.Mcl-1 represents an important survival factor for pancreatic cancer. In this study, Abulwerdi, Liao, and colleagues reported the preclinical data for a novel, selective small molecule Mcl-1 inhibitor, UMI-77, that targets the BH3-binding groove of Mcl-1. UMI-77 potently inhibits in vitro and in vivo pancreatic cancer growth by antagonizing Mcl-1 function and inducing Bax/Bak-dependent apoptosis. Western blot analysis in tumor remnants revealed enhancement of proapoptotic markers and significant decrease of survivin. These data provide evidence of Mcl-1 as a potential therapeutic target for pancreatic cancer and UMI-77 is currently being evaluated in combination with chemotherapy and radiotherapy.One of the major mechanisms underlying antimicrotubule drug (AMD) resistance involves acquired inactivation of the spindle assembly checkpoint (SAC). In this study, Miao, Wu, and colleagues report that synuclein gamma (SNCG), highly expressed in cancer cells but not in normal epithelium, is sufficient to induce AMD resistance in breast cancer through inhibiting the activity of spindle checkpoint kinase BubR1. SNCG-overexpressed cancer cells have a reduced ability to initiate and maintain proper mitotic arrest, which leads to AMD resistance by premature exit, before cells initiate apoptosis. These findings provide the basis for targeting SNCG in overcoming AMD resistance in cancer treatment.The UN1 monoclonal antibody (mAb) recognized CD43 glycoforms expressed in lymphoblastoid T-cell lines and solid tumors, and not in their normal counterpart. Here, Tuccillo, Palmieri, and colleagues demonstrated that UN1 mAb was endowed with ADCC activity in vitro and antitumor activity in vivo. By screening a phage-displayed random peptide library, they also identified the phagotope 2/165 as a mimotope of the UN1 antigen, which was able to elicit specific antibodies against the UN1/CD43 epitope in mice. These findings support the feasibility of using monoclonal antibodies to identify cancer-associated mimotopes and indicate the potential of cancer-associated CD43 as a target for immunotherapy.

Abstract 2917: Design, synthesis and biological evaluation of two chemical classes as novel small molecule Mcl-1 inhibitors

Abstract The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has a critical and distinct role(s) in maintaining cell survival and is emerging as an independent and promising therapeutic target. Using structure-based design, two classes of small molecule Mcl-1 inhibitors were developed with IC50 values ranging from 50 nM to 75 μM, based on the lead compounds identified from high throughput screening. The structure-activity relationships (SAR) of these compounds were analyzed and chemical features of both series that are important for potency and selectivity on Mcl-1 were identified. The HSQC-NMR spectroscopy studies combined with molecular docking and dynamics simulations demonstrated that both classes of compounds occupy the BH3 binding site in Mcl-1 protein mimicking two conserved hydrophobic residues from BH3 binding motif. The most potent analogues antagonize Mcl-1 on the functional level and they induce release of cytochrome c, inhibit cell growth and induce apoptosis in Bax/Bak-dependent manner in pancreatic and melanoma cancer cells with high levels of Mcl-1. The knowledge gained through these studies provides promise for future design and expansion of these series towards development of potent small-molecule Mcl-1 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2917. doi:1538-7445.AM2012-2917

Abstract 4851: Selective small molecule inhibition of anti-apoptotic MCL-1

Abstract BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. Anti-apoptotic members such as BCL-2, BCL-XL, and MCL-1 have been implicated in the initiation, progression, and chemoresistance of human cancer. The anti-apoptotic BCL-2/BCL-XL groove that binds and sequesters pro-apoptotic BH3 death helices has been successfully targeted by small molecules and peptides. Such compounds induce tumor cell apoptosis and are being advanced in clinical trials as promising next-generation cancer therapeutics. Notably, selective antagonists such as ABT-737 are highly effective at inducing apoptosis in BCL-2/BCL-XL-dependent cancers, but are rendered inactive by overexpression of MCL-1, a formidable chemoresistance protein that lies outside the molecule's binding spectrum. By screening a library of Stabilized Alpha-Helix of BCL-2 domains (SAHBs), we previously discovered that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor (Stewart et al., Nat Chem Biol, 2010). Here, we deployed this natural peptidic inhibitor of MCL-1 in a competitive binding screen to identify an MCL-1 inhibitor molecule (MIM) that displays exquisite selectivity in in vitro binding and functional assays. NMR analysis documented that MIM engages the canonical BH3-binding pocket of MCL-1. Importantly, MIM selectively triggers caspase 3/7 activation and apoptosis in a cancer cell line that is dependent on induced overexpression of MCL-1, but showed no activity in the isogenic cell line that is driven instead by overexpressed BCL-XL. Conversely, ABT-737 manifested activity in the BCL-XL-overexpressing cancer cells but had no effect on the corresponding MCL-1-dependent cells. Thus, we report the application of MCL-1 SAHB to identify a selective small molecule inhibitor of MCL-1 that exhibits pro-apoptotic activity in the specific context of MCL-1 dependence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4851. doi:1538-7445.AM2012-4851

Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1

A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu-Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.