1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2–p53 interaction: discovery and SAR

Parks, Daniel J.; LaFrance, Louis V.; Calvo, Raul R.; Milkiewicz, Karen L.; Gupta, Varsha; Lattanze, Jennifer; Ramachandren, Kannan; Carver, Theodore E.; Petrella, Eugene C.; Cummings, Maxwell D.; Maguire, Diane; Grasberger, Bruce; Lu, Tianbao

doi:10.1016/j.bmcl.2004.11.009

Cited by 164 publications

(133 citation statements)

References 18 publications

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“…We have reported previously the identification of novel small-molecule inhibitors of the Hdm2:p53 interaction using ThermoFluor microcalorimetry, which detects a shift in the intrinsic melting temperature of protein bound to compound (28,31,32). A benzodiazepinedione series identified from this screening effort was further optimized for in vitro potency in a fluorescence polarization assay that detects the displacement of fluorescently labeled p53 peptide from an amino-terminal fragment of the Hdm2 protein (28).…”

Section: Inhibitors Of the Hdm2:p53 Interaction Suppress Tumor Cell Pmentioning

confidence: 99%

“…We have focused on the discovery of small-molecule inhibitors of the Hdm2:p53 interaction and identified an active series of benzodiazepinediones (28,32). Members of this chemical series have been successfully cocrystallized with Hdm2 and shown to make critical binding contacts in the p53-binding pocket of Hdm2 (28).…”

Section: Tdp665759 Potentiates Doxorubicin In Cell Culture and In A37mentioning

confidence: 99%

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Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo

Koblish

Zhao

Franks

et al. 2006

Molecular Cancer Therapeutics

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The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC 50 s of 14 and 0.7 Mmol/L, respectively. These results correlated with the direct

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Section: Inhibitors Of the Hdm2:p53 Interaction Suppress Tumor Cell Pmentioning

confidence: 99%

Section: Tdp665759 Potentiates Doxorubicin In Cell Culture and In A37mentioning

confidence: 99%

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo

Koblish

Zhao

Franks

et al. 2006

Molecular Cancer Therapeutics

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156

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“…[15,16] Multicomponent reactions allow the building of complex molecular scaffolds in a more efficient way than by classical, two-component chemistry. [17,18] In this context, the most active research area is probably on transformations that use isonitriles as key precursors, one of the most widely used transformations being the Ugi reaction.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction

et al. 2014

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An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 μM, EC50 =3.63 μM) and 22 (IC50 =1.37 μM, EC50 =6.90 μM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.

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“…Aryl amines exhibit a wide range of biological activities such as P2X7 receptor antagonists 9 , HDM2-p53 protein-protein antagonists 10 , MCH1 receptor antagonist 11 The structure of synthesized compounds were assigned based on Elemental analysis, I.R. 1 H-NMR and Mass spectral data.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Antimicrobial Evaluation of Schiff’s Base and Aryl Aminomethyl Derivatives

Kansagara

Dangar

Shah

2016

ILCPA

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1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2–p53 interaction: discovery and SAR

Cited by 164 publications

References 18 publications

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo

Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction

Synthesis, Characterization and Antimicrobial Evaluation of Schiff’s Base and Aryl Aminomethyl Derivatives

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