Structure–activity relationship and antitumor activity of thio-benzodiazepines as p53–MDM2 protein–protein interaction inhibitors

Guo, Zizhao; Zhuang, Chunlin; Zhu, Lingjian; Zhang, Yongqiang; Yao, Jing; Dong, Guoqiang; Wang, Shengzheng; Liu, Yang; Chen, Hai; Sheng, Chunquan; Miao, Zhenyuan; Zhang, Wannian

doi:10.1016/j.ejmech.2012.08.003

Cited by 35 publications

(20 citation statements)

References 20 publications

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“…Another study by Wang and co-workers in 2012 investigated the efficacy of nutlin-3a (Table 4) treatment in osteosarcoma cell lines both in vivo and in vitro [109]. Employing three osteosarcoma cell lines [U-2 OS (wt p53), SaOS2 (null p53), MG63 (mut-p53)], the authors deciphered that activation of the p53 pathway due to the disruption of p53-MDM2-interaction by nutlin-3a depends on the presence of wt-p53 [109].…”

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

“…Employing three osteosarcoma cell lines [U-2 OS (wt p53), SaOS2 (null p53), MG63 (mut-p53)], the authors deciphered that activation of the p53 pathway due to the disruption of p53-MDM2-interaction by nutlin-3a depends on the presence of wt-p53 [109]. Nutlin-3a stabilized p53 and led to dose-dependent anti-proliferative and cytotoxic effects, inducing cell cycle arrest at G1 phase and apoptosis both in vivo and in vitro [109]. Significant apoptosis and increased G1 phase fractions were detected, if treated with 10 µM nutlin-3a.…”

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

“…Significant apoptosis and increased G1 phase fractions were detected, if treated with 10 µM nutlin-3a. Further treatment with nutlin-3a significantly upregulated p53 and p21 levels in osteosarcoma cells [109]. In a quest to investigate, whether nutlin-3a suppresses growth of xenograft tumors in nude mice, Wang et al showed that it was well tolerated at a daily dosage of 25 mg/kg administered intraperitoneally for 14 days.…”

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

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The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.

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Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

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The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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“…44 A second example is shown in the very recent report on the activity of thio-benzodiazepines {21, 22} as nanomolar level inhibitors of the p53-MDM2 protein-protein interaction. 45 Other relatively simple structures such as a terphenyl {23} moiety mimics an α-helix. 46 In the absence of crystal structures, it is possible to use tools that help predict structure from sequence data-enabling anakysus.…”

Section: Inhibitors Of Protein-protein Interactionsmentioning

confidence: 99%

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

Newman¹,

Cragg²

2014

Natural Products

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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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Structure–activity relationship and antitumor activity of thio-benzodiazepines as p53–MDM2 protein–protein interaction inhibitors

Cited by 35 publications

References 20 publications

The role of p53 in cancer drug resistance and targeted chemotherapy

The role of p53 in cancer drug resistance and targeted chemotherapy

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

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

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