Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

Wang, Wei; Qin, Jiang‐Jiang; Voruganti, Sukesh; Wang, Ming Hai; Hl, Sharma; Patil, Shivaputra A.; Zhou, Jianwei; Wang, Hui; Mukhopadhyay, Debabrata; Buolamwini, John K.; Zhang, Ruiwen

doi:10.1053/j.gastro.2014.07.001

Cited by 69 publications

(107 citation statements)

References 45 publications

(73 reference statements)

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“…In addition, undesirable toxicity was observed in mice after administering BA-TPQ (a formulation of dispersed BA-TPQ in a mixture of PEG400/ethanol/0.9% saline [8,9]. Recent investigations identifying the potential sites of accumulation to elucidate the observed BA-TPQ toxicity have revealed a high accumulation of BA-TPQ in the lungs, kidneys, and spleen of the mice [10,11]. Thus, an active drug delivery system for BA-TPQ is needed to improve anticancer efficacy and minimize side effects.…”

Section: Introductionmentioning

confidence: 99%

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

et al. 2017

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We report a novel delivery platform for a highly potent anticancer drug, 7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ), using pH- and redox-sensitive poly(methacrylic acid) (PMAA) hydrogel cubes of micrometer size as the encapsulating matrix. The hydrogels are obtained upon cross-linking PMAA with cystamine in PMAA/poly(N-vinylpyrrolidone) multilayers assembled within mesoporous sacrificial templates. The BA-TPQ-loaded hydrogels maintain their cubical shape and pH-sensitivity after lyophilization, which is advantageous for long-term storage. Conversely, the particles degrade in vitro in the presence of glutathione (5 mM) providing 80% drug release within 24 h. Encapsulating BA-TPQ into hydrogels significantly increases its transport via Caco-2 cell monolayers used as a model for oral delivery where the apparent permeability of BA-TPQ-hydrogel cubes was ~2-fold higher than that of BA-TPQ. BA-TPQ-hydrogel cubes exhibit better anticancer activity against HepG2 (IC50=0.52 μg/mL) and Huh7 (IC50=0.29 μg/mL) hepatoma cells with a 40% decrease in the IC50 compared to the non-encapsulated drug. Remarkably, non-malignant liver cells have a lower sensitivity to BA-TPQ-hydrogel cubes with 2-fold increased IC50 values compared to those of cancer cells. In addition, encapsulating BA-TPQ in the hydrogels amplifies the potency of the drug via down-regulation of MDM2 oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells. Moreover, enhanced inhibition of MDM2 protein expression by BA-TPQ-hydrogel cubes is independent of p53-status in Huh7 cells. This drug delivery platform of non-spherical shape provides a facile method for encapsulation of hydrophobic drugs and can facilitate the enhanced efficacy of BA-TPQ for liver cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

et al. 2017

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“…The developed LC-MS/MS method was validated for linearity, accuracy, precision, recovery, and matrix effect, according to USA FDA guidelines [20]. Firstly, the specificity of the method was assessed by analyzing blank plasma spiked with SP-141 to observe the possible endogenous interference from plasma with the analyte.…”

Section: Methodsmentioning

confidence: 99%

“…This compound is different from conventional MDM2 inhibitors in the fact that it directly binds to the MDM2 protein, induces its degradation, and inhibits its oncogenic functions in cancer cells. Further studies have also indicated that SP-141 has high potency against human breast and pancreatic cancers, without any observable toxicity at doses leading to tumor regression [20]. Therefore, we see that SP-141 shows good promise for development as a novel anticancer therapeutic agent.…”

Section: Introductionmentioning

confidence: 90%

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A quantitative LC-MS/MS method for determination of SP-141, a novel pyrido[b]indole anticancer agent, and its application to a mouse PK study

Nag

Qin

Patil

et al. 2014

Journal of Chromatography B

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In the present study, a specific and sensitive liquid chromatography-triple quadrupole mass spectrometry method was developed and validated for the determination of SP-141, a novel pyrido[b]indole anticancer agent. After a liquid-liquid extraction with n-hexane–dichloromethane-2-propanol (20:10:1, v/v/v) mixture, the analyte was separated on a Kinetex C18 column (50 × 2.1 mm, 2.6 μm) with mobile phases comprising of water (0.1% formic acid, v/v) and acetonitrile (0.1% formic acid, v/v) at a flow rate of 0.4 mL/min. The test compound (SP-141) and the internal standard (SP-157) were analyzed in the multiple reaction-monitoring mode using the mass transitions m/z 325.1 → 282.0. The method was linear in the concentration range of 0.648-162 ng/mL with coefficients of determination (R2) of 0.999 in mouse plasma. The lower limit of quantification was 0.648 ng/mL. The intra- and inter-day assay precisions (coefficient of variation, %CV) were less than 4.2% and accuracies (relative error, %RE) ranged from −6.1% to 2.1%. The extraction recoveries were between 97.1-103.1% and the relative matrix effect was minimal. In addition, SP-141 was found to be stable in the plasma after three freeze-thaw cycles, at 37°C and 4°C for 24 h, and at −80 °C for 4 weeks. It was also stable in the stock solution at room temperature for 24 h and after preparation in the autosampler for 36 h. The validated method was successfully applied to an initial pharmacokinetic study of SP-141 in CD-1 mice following intraperitoneal and intravenous administrations.

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“…For prediction, the pancreatic cell lines AsPC-1 (p53 null), BxPC-3 (p53-mutant), CAPAN-1 (p53-mutant), MIA-PaCa-2 (p53-mutant), and CAPAN-2 (p53-wild type) were selected on the basis on previous biological evaluation studies for p53-MDM2 inhibitors [23,24]. DiPCell server reported earlier and known for prediction of anticancer activity (IC 50 values) precisely for various types of pancreatic cell lines (http://crdd.osdd.net/raghava/ dipcell/) [11].…”

Section: Ic 50 Values Prediction Of Nutlin-3a Sar405838 and L0-l11mentioning

confidence: 99%

Design and Anticancer Activity Prediction of Dihyropyrimidinone Based Novel Inhibitors of P53-Mdm2 Interaction

Nayak

Khatik

Narang

et al. 2017

Asian J Pharm Clin Res

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Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using "Cancer IN" server. Methods:In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC 50 , anticancer activity, and toxicity profile were designed. Lead L11 was obtained after sequential isosteric replacement of functional groups for optimization in compound L0. Results:The docking scores of L3-L11 found to be in range of 21-25 close to docking score 25 of SAR405838 and better than nutlin-3a. MDM2 binding affinity values (37-78 Kcal/mol) of all ligands were also found to better than that of nutlin-3a (37 Kcal/mol). Surprisingly, MDM2 binding affinity of L11 (78 Kcal/mol) found to be equal to that of SAR405838 and 2-fold greater than nutlin-3a.Conclusion: These data indicating that L11 as a potential lead from dihydropyrimidinones for inhibition of p53-MDM2 interaction.

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Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

Cited by 69 publications

References 45 publications

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

A quantitative LC-MS/MS method for determination of SP-141, a novel pyrido[b]indole anticancer agent, and its application to a mouse PK study

Design and Anticancer Activity Prediction of Dihyropyrimidinone Based Novel Inhibitors of P53-Mdm2 Interaction

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