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Proc Natl Acad Sci U S A. Sep 13, 2011; 108(37): 15074-15078.
Published online Aug 1, 2011. doi:  10.1073/pnas.1015247108
PMCID: PMC3174672
Chemistry, Cell Biology

Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin

Abstract

Migrastatin is a biologically active natural product isolated from Streptomyces that has been shown to inhibit tumor cell migration. Upon completion of the first total synthesis of migrastatin, a number of structurally simplified analogs were prepared. Following extensive in vitro screening, a new generation of analogs was identified that demonstrates substantially higher levels of in vitro inhibitory activity, stability and synthetic accessibility when compared to the parent natural product. Herein, we describe two promising ether-derivative analogs, the migrastatin core ether (ME) and the carboxymethyl-ME (CME), which exhibit high efficacy in blocking tumor cell migration and metastasis in lung cancer. These compounds show an in vitro migration inhibition in the micromolar range (IC50: ME 1.5 to 8.2 μM, CME 0.5 to 5 μM). In a human small-cell lung carcinoma (SCLC) primary xenograft model, ME and CME compounds were found to be highly potent in inhibiting overall metastasis even at the lowest dosage used (degree of inhibition: 96.2% and 99.3%, respectively). Together these very encouraging findings suggest that these analogs have promise as potent antimetastatic agents in lung cancer.

Our laboratories have had a long-term interest in small-molecule natural products (SMNPs), from the standpoint of both synthesis and biological evaluation. At the level of chemical synthesis, these types of targets have provided a host of challenges, in terms of issues of gross structure and stereochemical presentation. Moreover, SMNPs often constitute unusually promising opportunities for discovery of novel biological profiles, which might, upon optimization, be exploitable for pharmaceutical ends. It was for such considerations that we took considerable interest in reports describing the isolation of a tumor cell migration inhibitor, termed migrastatin (1), from fermentation sources (14).

From the perspective of a synthetic challenge, the structure of migrastatin is such that it fits in well with our ideas about modulating acyclic stereochemistry through systematic disconnection of pyranoid rings generated from the Lewis acid-catalyzed diene aldehyde cyclocondensation (LACDAC) reaction (5). Aside from the need to deal with the macrolactone matrix of migrastatin, a workable total synthesis must be responsive to the issue of appending the glutarimide containing side chain in a stereodefined manner.

In the context of providing a possible platform for pharma discovery, migrastatin was of particular interest to us. The migration of metastatic tumor cells from the primary tumor to outlying sites and organs is a poor prognosis feature of many cancers and is associated with resistance to therapy. Cell migration is clearly relevant to a host of critical biological functions (cf. inter alia: embryonic development, organogenesis, and homeostasis). Unfortunately, the deregulation of this complex process is also involved in cancer progression (tumor angiogenesis and metastasis). Tumor angiogenesis (the angiogenic switch) is likely to set the stage for cancer cell invasion and metastasis. Though the activity of migrastatin in a wound-healing assay was only ca. 29 μM (IC50), it was hoped that our previously described modality of diverted total synthesis (DTS) might lead to enhanced potency in the context of a workable therapeutic index. The first stage in our SMNP-oriented discovery strategy is to focus on the total synthesis challenge. From there we go on to the exploration of “high pedigree” cognate molecular space, accessible through DTS. This discovery platform is in keeping with our notion that a molecular editing exercise with a biologically active natural product as the primary “first draft” is more likely to be fruitful than high-throughput exercises driven by stochastic modalities.

Critical to our synthetic planning goals was the design of a concise, scalable, and flexible route to migrastatin that would allow for verification of its reported structure and confirmation of its alleged biological functions while also providing maximum flexibility for exploring SAR profiles in surrounding high pedigree molecular space. From the planning phase there emerged a suitable strategy wherein migrastatin would be assembled in a convergent fashion from readily available building blocks.

The reduction to practice of these deliberations is captured in Scheme 1. Thus, union of aldehyde 2, readily obtained from an inexpensive chiral pool source, and diene 3 selectively afforded the C8-C10 stereotriad (4) en route to the migrastatin macrocyclic core. Following our protocols of the 1980s, reduction of the ketone followed by a Ferrier rearrangement of the resultant glycal served to install the Z-trisubstituted olefin of migrastatin (see 5). This key intermediate was advanced to migrastatin (1) in a straightforward manner as shown. Key transformations included: stereocontrolled anti-aldol reaction of 7 and 6; introduction of the glutarimide funtionality via Horner-Wadworth–Emmons (HWE) reaction (9 + 10 → 11); and construction of the macrolactone through ring closing metathesis (RCM) (6). Indeed, the high level of congruence of the spectroscopic properties of the synthetic product and the fermentation-derived natural product left no cause to doubt its identity.

Scheme 1.
Total synthesis of migrastatin (1).

Upon completing the first total synthesis of migrastatin, we confirmed the reported in vitro cell migration inhibitory activity with our synthetic material (6). We then set out to prepare and evaluate a range of analogs through reliance on the logic of DTS. Initial studies focused on discerning the biological roles of the glutarimide N-H functionality and the C2-C3 double bond, which has the potential, in principle, to act as a Michael acceptor. Interestingly, analogs incorporating either a methyl cap on the glutarimide moiety or saturation at C2-C3 showed approximately similar levels of migration inhibitory activity compared to the parent natural product, suggesting that these structural features are not central to the biological function of the natural product (7). In light of these findings, we next designed a menu of structurally simplified migrastatin analogs lacking the glutarimide side chain. We note, in passing, that the success of our ongoing migrastatin program serves to illustrate the unique power and flexibility of the DTS approach to lead agent optimization.

With regard to SMNPs as a major resource for pharma development, it should be well appreciated that the reasons as to why organisms or plants biosynthesize such secondary metabolites are far from clear. It is likely that SMNPs emerge with proclivity for binding to biolevel targets, such as proteins, oligosaccharides, or nucleic acids—perhaps for regulatory purposes or as defensive resources against various challenges from potential predators. Certainly, there is no reason to believe that the SMNPs have been optimized for the purposes that the pharma scientist might have in mind. Moreover, the SMNP may not be optimized even for its intended mission. The structure of the SMNP that does arise may well reflect the limitations of the available biosynthetic pathway. These catabolic mechanisms are not readily diverted for purposes of med chem level analog synthesis.

Returning to migrastatin, we were particularly anxious to explore its adjoining molecular terrain. We sensed that approaches to analog synthesis, by manipulations starting with the intact natural product, would not readily permit access to the wide array of analogs that we sought. These are clear limitations in the available chemistry that would be needed to alter the sensitive migrastatin structure in the ways we envisioned. Modification of the biosynthetic machinery (via polyketide synthases) (8) to gain access to the substrates we wished to explore was not practical. Happily, we were able to synthesize what we needed from an advanced intermediate en route to migrastatin. As will be shown, several of our migrastatin-associated compounds, readily accessible through DTS, have shown great promise in preclinical settings. The overall program that emerged is summarized in Scheme 2.

Scheme 2.
DTS of migrastatin analogs.

The analogs shown in Scheme 3 were synthesized through DTS from a common advanced intermediate. We were pleased to find that several of the structurally simplified synthetic analogs exhibited higher levels of in vitro inhibitory activity than the parent natural product. Analysis of a series of macrolactone derivatives (1316) revealed the migrastatin core (13) and 2,3-dihydro-migrastatin core (14) to be particularly active in an in vitro chamber cell migration assay. However, the hydrolytic instability of these analogs served to limit enthusiasm for their further development. Lactones 15 and 16, designed with a view toward enhancing hydrolytic stability, were found to exhibit poor in vitro activity (8).

Scheme 3.
Migrastatin-based macrolides. Numbers in parentheses represent migratory inhibition activity (IC50 = half maximal inhibitory concentration) against 4T1 mouse breast cancer cells in a chamber cell migration assay.

In light of these findings, we sought to “edit” out the problematic lactone functionality. Thus, migrastatin core ketone (17), lactam (18), and ether (19) analogs (9) were prepared and evaluated in a chamber cell migration assay. As shown in Scheme 3, each of these compounds exhibited highly promising levels of in vitro migration inhibitory activity. A number of ketone-derived analogs also performed well in the migration assay (2024). On the basis of their demonstrated activity, stability, and synthetic accessibility, compounds 17, 18, and 19 were selected for further in vitro and in vivo evaluation.

Further in vitro studies of migrastatin ketone (17), lactam (18) and core ether (ME, 19) revealed the ketone (17, IC50 = 0.023–0.35 μM) and ME (19, IC50 = 0.27–0.38 μM) to be generally more effective than the lactam (18, IC50 = 0.17–2.7 μM) in inhibiting transwell migration of a range of tumor cell lines. Importantly, we were pleased to observe that in all cases, an approximately 1,000-fold higher concentration of migrastatin analog was required to achieve comparable inhibition of normal human mammary epithelial MCF10A cells.

A range of preliminary in vivo studies was undertaken to further assess the therapeutic prospects of our migrastatin lead compounds. Due to its similarity to human breast cancer and its propensity to spontaneously metastasize to a variety of target organs, including the lung, bone, brain, and liver, the 4T1 mouse mammary tumor serves as a useful model. In a key study, BALB/c mice implanted with 4T1 cells were treated on day 10 following implantation with migrastatin core ketone (17) or lactam (18) at 10 mg/kg or 20 mg/kg (10). Following sacrifice 20 d later, the amount of lung metastasis in mice treated with either 17 or 18 was reduced by 91–99% relative to the control group. This effect is attributed, largely if not totally, to the inhibition of mestastatic spread, because no significant difference in primary tumor progression was observed following treatment with these drugs.

The migrastatin core ether (ME, 19), which we consider to be the most promising of the first-generation analogs on the basis of its in vitro activity, physical properties, ease of preparation, and apparent biological stability, has been the subject of a number of in vivo investigations. In one key study, NOD/SCID mice were injected in the abdominal mammary fat pad with MDA231 breast cancer cells. On day 1, groups of mice were treated with low-dose (40 mg/kg) or high-dose (200 mg/kg) ME (i.p. 3× weekly). After four weeks, the primary tumors were resected and the mice were subjected to weekly bioimaging for metastatic tumor. One week following resection, the control mice (treated with PBS buffer) showed extensive metastases, while both groups of ME-treated mice presented significant reduction in metastasis (88–93%). Although the low-dose ME-treated mice showed liver and lung metastasis by nine weeks, no detectable metastatic growth was observed in the high-dose cohort. In accordance with our previous findings, treatment with ME did not significantly attenuate growth of the primary mammary tumor. Similarly positive results were observed with other breast cancer models, including the LM2 cell line, which demonstrate decreased metastasis in the lungs (11).

On the basis of these promising in vivo findings in breast cancer cell lines, we sought to expand the scope of our studies to encompass other types of metastatic tumors. We describe herein some encouraging findings that suggest that ME may serve as a viable tumor cell migration inhibitory agent against metastatic small-cell lung carcinoma (SCLC).

Moreover, in an effort to identify ME-based analogs with enhanced bioavailability and pharmacostability, we also synthesized the stabilized and more formulatable carboxymethyl derivative of ME (CME, 25), which we hoped might exhibit improved in vivo activity. We disclose herein the results of in vitro and in vivo studies, in which 25 exhibits very promising efficacy in blocking cell migration and tumor metastasis.

Results and Discussion

In Vitro Evaluation of ME (19) and CME (25).

In order to evaluate the antimetastatic properties of our recently synthesized ME analog, carboxymethyl-ME (CME, 25), we assessed its ability to inhibit in vitro cancer cell migration in a wound-healing assay and its chemotaxis in a transwell migration assay. As shown in Fig. 1, ME (19) and CME (25) at 100 μM almost completely blocked migration of human non-small-cell lung carcinoma (NSCLC) A549 cells in response to a scratch wound. At submicromolar concentrations, CME was still quite effective (32% inhibition of migration).

Fig. 1.
Inhibition of A549 lung cancer cell lines migration in an “in vitro wound-healing” assay by migrastatin ether (ME) and carboxymethyl-migrastatin ether (CME). A549 cancer cells were grown as a nearly confluent monolayer culture and then ...

To further characterize these compounds, chemotaxis in response to a serum gradient in a modified Boyden chamber system was used to evaluate the panel of NSCLC lines. This assay provided reproducibly robust data, allowing dose-response studies to be carried out to determine the IC50. As shown in Fig. 2 and Table 1, ME and CME efficiently blocked the migration of human lung cancer cells through the 8 μm pore insert in response to the serum gradient. Comparatively, CME exhibited lower IC50 values (0.5 to 5 μM) than ME compound (1.5 to 8.2 μM) against A549, H1975, and H299 cancer cells. Because we noticed a mild toxicity and effects on cell proliferation in the millimolar range, experiments with CME and ME at 1 mM or more were not included for the IC50 calculation. Collectively, these results demonstrate a very sensitive response in term of in vitro migration inhibition that is more than 2 orders of magnitude less than the concentration found to produce cytotoxicity.

Fig. 2.
Inhibition of transwell lung cancer cell lines migration by migrastatin ether (ME) and carboxymethyl-migrastatin ether (CME). Cancer cell chemotaxis was performed with 105 H1975 cells toward a serum gradient or in the absence of a serum gradient in a ...
Table 1.
Inhibition of transwell lung cancer cell lines migration by migrastatin ether (ME) and carboxymethyl-migrastatin ether (CME) (IC50 in µM)

Evaluation of the Antimetastatic Activity of ME (19) and CME (25) in a Human SCLC Xenograft Model.

We next examined the capacity of our lead compounds to inhibit tumor metastasis in a human SCLC primary xenograft model. These cells, in primary and subsequent in vivo passages in NOD/SCID mice, tend to form liver metastases. The tumor cells were stably transduced with a triple-fusion protein reporter construct (AC3-TGL) and then transplanted by subcutaneous injection with matrigel into NOD/SCID IL2R gamma null (NSG) mice.

Starting 1 d prior to the inoculation of tumor cells, groups of mice were treated with ME at doses of 10 mg/kg, 40 mg/kg, or 200 mg/kg, or with CME at 12 mg/kg or 49 mg/kg (note: dosage levels were adjusted to account for differences in molecular weight: 1 mg ME = 1.2 mg CME). Control mice were treated with DMSO vehicle. The compounds were administered by i.p. injection every 3 d, from day -1 to day 55 following cell injection (n≥5 mice per group). During this time, tumor burden and metastatic spread were monitored by serial noninvasive bioluminescent imaging (BLI) at days 14, 23, 30, 40, and 50. At day 55, the mice were sacrificed and the metastatic spread of tumor cells to the lungs, liver, heart, kidneys, and spleen was assessed by ex-vivo BLI on the removed organs.

As expected, treatment with ME and CME did not significantly affect tumor growth kinetics at the primary site of injection (Fig. S1). In the ME-treated cohorts, some toxicity was observed, resulting in the deaths of three mice in the 200 mg/kg group and two mice each in the 10 mg/kg and 40 mg/kg groups prior to the study endpoint. In contrast, no toxicity was observed in either cohort of CME-treated mice.

At the study endpoint, the potential metastatic sites (liver, lungs, spleen, heart, and kidneys) were surgically resected and the luciferase activity quantified by ex-vivo BLI. Compared to the control group, the mice treated with 10 mg/kg or 40 mg/kg ME exhibited significantly decreased levels of overall metastasis, with calculated inhibition factors of 96.2% (p-value = 0.0095) and 99.1% (p-value = 0.0043), respectively (Fig. 3 and Table S1). An even greater degree of metastasis inhibition (99.8%) was seen in the two surviving mice treated with high-dose ME (200 mg/kg). Bioimaging of mice after removal of the various organs showed no other metastatic sites.

Fig. 3.
CME comparison with ME for inhibition of metastasis in a human primary SCLC xenograft model. AC3-TGL cells were transplanted by subcutaneous ventral injection into NSG mice. Xenografted mice were treated with indicated dosages of CME or ME every three ...

As hoped, the CME analog was found to be significantly more potent than the parent compound, ME, in inhibiting in vivo tumor metastasis. Thus, as shown in Fig. 3, treatment with low-dose CME (12 mg/kg) led to suppression of metastasis by 99.3%, rendering CME approximately four times more potent than ME at the lowest dosage level. Moreover, at 49 mg/kg, tumor metastasis was inhibited by 99.8%. These findings, which are consistent with our in vitro results, lend support to our hypothesis that appendage of a carboxymethyl functionality onto the ME scaffold provides enhanced migratory inhibition activity. We are currently pursuing further preclinical testing of CME, which we view as a particularly promising candidate in the treatment of tumor metastasis.

In summary then, collaborative chemistry and cell biology studies have led to the identification of several compounds worthy of serious consideration as inhibitors of metastasis. Though the compounds do not appear to attack the primary tumors, one could readily imagine considerable clinical benefits from an agent that blocks metastasis. Applications of an antimetastatic agent might well be particularly helpful following resection of the primary tumor via surgery, chemotherapy, or radiation.

Of course, the effort could gain much from an insight as to the mode of action, at least of our lead compounds. A recent claim by Huang and coworkers that has attracted much attention identified the intracellular protein, FASCIN, as the primary target (12). We have questioned the robustness of the crystallographically based conclusion arising from an incorrect representation of the alleged small-molecule “migrastatin” embedded in the FASCIN (13). Moreover, it might be expected that the incorporation of a low pKa carboxylic acid in the CME analog would, in fact, lead to reduced cell penetration. This finding could be construed as supporting the notion of a primary protein target residing on the cell surface, rather than an intracellular protein, such as FASCIN. Our laboratories, in collaboration with others, are continuing to pursue these issues.

Materials and Methods

Cells and Primary Tumor.

Human non-small-cell lung carcinoma (NSCLC) cell lines were obtained from the American Type Culture Collection (Manassas, VA) or the National Cancer Institute: NCI-A549, NCI-H1975, NCI-H299, NCI-H1993, and NCI-H1373 (adenocarcinoma), NCI-H647 and NCI-H1703 (squamous cell carcinoma of the lung [SCC]). Human primary small-cell lung carcinoma (SCLC) cells, transduced with thymidine kinase/green fluorescent protein/luciferase triple-fusion gene and named AC3-TGL, were previously described (14) and obtained from J. Massagué. All lung cancer cell lines were grown in M5-medium consisting of DME:F12 supplemented with 25 mM Hepes, 2.2 g/L sodium bicarbonate. Primary SCLC cells were grown in RPMI supplemented with 10 mM hepes, 1.5 g/L sodium bicarbonate and 4.5 g/L glucose (Media Preparation Core Facility, MSKCC). Both media were supplemented with 10% (v/v) fetal calf serum, 2 mM L-Glutamine and 500 U/mL penicillin and streptomycin.

Proliferation Assay.

Cells were plated in flat-bottom 96-well plates at a density of 5 × 103 cells per well in 150 μL of complete medium. When used, drugs or DMSO (vehicle) were added to the medium at 0.2%. After 3 and 6 d of treatment, cell proliferation was assessed by adding CellTiter 96 AQueous Assay reagent (Promega) to each well according to the manufacturer’s instructions. After 2 h incubation at 37 °C, cell proliferation was determined by measuring the absorbance at 490 nm, using a 96-well plate reader.

Migration Assay.

Cancer cell chemotaxis was performed toward a serum gradient in a modified Boyden chamber consisting of a cell culture insert (6.4 mm diameter, 8-μm pore polyethylene tetraphtalate membrane, [Becton Dickinson]) seated in each well of a 24-well companion plate (Becton Dickinson). Briefly, cancer cells were grown as subconfluent monolayer cultures then starved for 36 h in serum-free M5 medium. After detachment and dissociation with 5 mM EDTA, single-cell suspensions were prepared by filtration through a 35 μm mesh cell strainer (Becton Dickinson). Cells were counted and a total of 10 (8) cells suspended in serum-free medium were seeded into the upper chamber of an insert, then positioned in a 24-well plate containing medium with or without 10% serum. When used, drugs or DMSO (vehicle) were added to the medium at 0.2% in both chambers. Migration assays were carried out for 12 h in a humidified incubator at 37 °C with 5% CO2. Cells were then fixed with 3.7% formaldehyde, permeabilized with ice cold methanol and stained with a 0.2% crystal violet solution. Nonmigratory cells on the upper side of the insert were removed with a cotton swab. For quantification, three randomly selected fields on the lower side of the insert were photographed at 4X and 20X magnification using computer-assisted microscopy and analyzed with CellProfiler2.0 cell image analysis software (15). The migration in response to the test condition was calculated relative to the DMSO vehicle control.

In Vitro Wound-Healing Assay.

Migration of cancer cells was measured using an “in vitro wound-healing assay” (or scratch assay) performed in a 12-well plate (Becton Dickinson). Briefly, cancer cells were seeded at a density of 5–10 × 104 cells per well, grown to near confluent monolayers in 10% serum-supplemented M5 medium, and then starved overnight in a low serum medium (0.5% FCS). Perpendicular wounds were scratched through the cell monolayer using a sterile 200 μL pipette tip. The cells were then washed twice very gently using PBS, and the scratched areas were photographed at 4X and 20X magnification using computer-assisted microscopy. PBS was removed and replaced with 2 mL of media with or without 2% FCS, and containing drugs or DMSO (vehicle control) at 0.2% (v/v). After 12–24 h in a humidified incubator at 37 °C with 5% CO2, cells were fixed with 3.7% formaldehyde, permeabilized with ice cold methanol, and stained with a 0.2% crystal violet solution. Each well was photographed at 4X and 20X magnification and the pictures analyzed with CellProfiler2.0 cell image analysis software as previously described (15). The migration in response to the test condition was calculated as cell coverage of the original cell-free zone and related to DMSO vehicle control.

In Vivo Xenograft Model of Lung Cancer Metastasis.

A human primary SCLC xenograft model was developed in 10- to 14-week-old male NSG mice. Primary tumor samples were obtained after patient informed consent under an MSKCC IRB approved protocol. AC3-TGL tumor cells growing as clumps were dissociated into a single-cell suspension by Trypsin/Collagenase IV (Invitrogen) sequential treatment. Xenografts were performed by subcutaneous ventral injection of 500 AC3-TGL cells in serum-free medium mixed with Matrigel (Becton Dickinson).

One day prior to the tumor cell injection, mice were pretreated with either: (i) migrastatin ether (ME) at a dose of 10 mg/kg, 40 mg/kg or 200 mg/kg per mouse; (ii) carboxymethyl-ME (CME) at a dose of 12 mg/kg or 49 mg/kg; or (iii) DMSO vehicle control (n≥5 mice per group). Drug treatment was delivered by intraperitoneal injection every 3 d starting from day -1 after cell injection to day 55. During this time, the tumor burden and metastatic spread were monitored by bioluminescence imaging (BLI) at day 14, 23, 30, 40, and 50. At day 55 (endpoint), the mice were killed and the metastatic spread of tumor cells to the lungs, liver, heart, kidneys, and spleen was assessed by ex-vivo BLI on the surgically resected organs.

All animal experiments were done in accordance with a protocol approved by the MSKCC Institutional Animal Care and Use Committee. All animals were maintained in a pathogen-free animal housing facility at MSKCC.MSKCC. Scheme

Scheme 4.
Migrastatin ether (ME) and carboxymethyl-migrastatin ether (CME).

Supplementary Material

Supporting Information:

Acknowledgments.

We thank J. Massagué for providing human primary SCLC cells. Support for this research was provided by the National Institutes of Health (CA103823 to S.J.D.).

Footnotes

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1015247108/-/DCSupplemental.

References

1. Nakae K, et al. Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929-43F. J Antibiot. 2000;53:1130–1136. [PubMed]
2. Nakae K, et al. Migrastatin, a novel 14-membered lactone from Streptomyces sp. MK929-43F. J Antibiot. 2000;53:1228–1230. [PubMed]
3. Takemoto Y, et al. Migrastatin, a novel 14-membered ring macrolide, inhibits anchorage-independent growth of human small cell lung carcinoma Ms-1 cells. J Antibiot. 2001;54:1104–1107. [PubMed]
4. Nakamura H, et al. Absolute configuration of migrastatin, a novel 14-membered ring macrolide. J Antibiot. 2002;55:442–444. [PubMed]
5. Danishefsky SJ. Reflections on organic synthesis: The evolution of a general strategy for the stereoselective construction of polyoxygenated natural products. Aldrichimica Acta. 1986;19:59–69.
6. Gaul C, Njardarson JT, Danishefsky SJ. The total synthesis of (+)-migrastatin. J Am Chem Soc. 2003;125:6042–6043. [PubMed]
7. Njardarson JT, Gaul C, Shan D, Huang XY, Danishefsky SJ. Discovery of potent cell migration inhibitors through total synthesis: Lessons from structure—activity studies of (+)-migrastatin. J Am Chem Soc. 2004;126:1038–1040. [PubMed]
8. Ju J, Lim SK, Jiang H, Seo JW, Shen B. Iso-migrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK30424 scaffolds. J Am Chem Soc. 2005;127:11930–11931. [PubMed]
9. Oskarsson T, et al. Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: In vivo and mechanistic studies on the migrastatin core ether analog. J Am Chem Soc. 2010;132:3224–3228. [PMC free article] [PubMed]
10. Shan D, et al. Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. Proc Natl Acad Sci USA. 2005;102:3772–3776. [PMC free article] [PubMed]
11. Minn AJ, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–524. [PMC free article] [PubMed]
12. Chen L, Yang S, Jakoncic J, Zhang JJ, Huang XY. Migrastatin analogues target fascin to block tumor metastasis. Nature. 2010;464:1062–1066. [PMC free article] [PubMed]
13. Nagorny P, et al. Confirmation of the structures of synthetic derivatives of migrastatin in the light of recently disclosed crystallographically based claims. Tetrahedron Lett. 2010;51:3873–3875. [PMC free article] [PubMed]
14. Rodina A, et al. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol. 2007;3:498–507. [PubMed]
15. Carpenter AE, et al. CellProfiler: Image analysis software for identifying and quantifying cell phenotypes. GenomeBiology. 2006;7:R100. [PMC free article] [PubMed]

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