Exploiting the Indole Scaffold to Design Compounds Binding to Different Pharmacological Targets

Several indole derivatives have been disclosed by our research groups that have been collaborating for nearly 25 years. The results of our investigations led to a variety of molecules binding selectively to different pharmacological targets, specifically the type A γ-aminobutyric acid (GABAA) chloride channel, the translocator protein (TSPO), the murine double minute 2 (MDM2) protein, the A2B adenosine receptor (A2B AR) and the Kelch-like ECH-associated protein 1 (Keap1). Herein, we describe how these works were conceived and carried out thanks to the versatility of indole nucleus to be exploited in the design and synthesis of drug-like molecules.

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Phosphorylation of murine double minute clone 2 (MDM2) protein at serine-267 by protein kinase CK2 in vitro and in cultured cells

Biochemical Journal ◽

10.1042/0264-6021:3550347 ◽

2001 ◽

Vol 355 (2) ◽

pp. 347 ◽

Cited By ~ 14

Author(s):

Majbrit HJERRILD ◽

Diane MILNE ◽

Nicolas DUMAZ ◽

Trevor HAY ◽

Olaf-Georg ISSINGER ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinase Ck2 ◽

Cultured Cells ◽

Mdm2 Protein ◽

Double Minute ◽

Murine Double Minute ◽

Kinase Ck2

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Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

Molecules ◽

10.3390/molecules26144213 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4213

Author(s):

Pankaj Sharma ◽

Chris LaRosa ◽

Janet Antwi ◽

Rajgopal Govindarajan ◽

Karl A. Werbovetz

Keyword(s):

Anticancer Agents ◽

Histone Deacetylases ◽

Biological Activities ◽

Structural Components ◽

Mdm2 Protein ◽

Drug Discovery And Development ◽

Design And Synthesis ◽

Wide Range ◽

Murine Double Minute ◽

High Polarity

Nitrogen-containing heterocyclic rings are common structural components of marketed drugs. Among these heterocycles, imidazole/fused imidazole rings are present in a wide range of bioactive compounds. The unique properties of such structures, including high polarity and the ability to participate in hydrogen bonding and coordination chemistry, allow them to interact with a wide range of biomolecules, and imidazole-/fused imidazole-containing compounds are reported to have a broad spectrum of biological activities. This review summarizes recent reports of imidazole/fused imidazole derivatives as anticancer agents appearing in the peer-reviewed literature from 2018 through 2020. Such molecules have been shown to modulate various targets, including microtubules, tyrosine and serine-threonine kinases, histone deacetylases, p53-Murine Double Minute 2 (MDM2) protein, poly (ADP-ribose) polymerase (PARP), G-quadraplexes, and other targets. Imidazole-containing compounds that display anticancer activity by unknown/undefined mechanisms are also described, as well as key features of structure-activity relationships. This review is intended to provide an overview of recent advances in imidazole-based anticancer drug discovery and development, as well as inspire the design and synthesis of new anticancer molecules.

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Phosphorylation of murine double minute clone 2 (MDM2) protein at serine-267 by protein kinase CK2 in vitro and in cultured cells

Biochemical Journal ◽

10.1042/bj3550347 ◽

2001 ◽

Vol 355 (2) ◽

pp. 347-356 ◽

Cited By ~ 14

Author(s):

Majbrit HJERRILD ◽

Diane MILNE ◽

Nicolas DUMAZ ◽

Trevor HAY ◽

Olaf-Georg ISSINGER ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinase Ck2 ◽

Cultured Cells ◽

Specific Inhibitor ◽

Mdm2 Protein ◽

Acidic Domain ◽

Double Minute ◽

Murine Double Minute ◽

Kinase Ck2

Murine double minute clone 2 oncoprotein (MDM2) is a key component in the regulation of the tumour suppressor p53. MDM2 mediates the ubiqutination of p53 in the capacity of an E3 ligase and targets p53 for rapid degradation by the proteosome. Stress signals which impinge on p53, leading to its activation, promote disruption of the p53-MDM2 complex, as in the case of ionizing radiation, or block MDM2 synthesis and thereby reduce cellular MDM2 levels, as in the case of UV radiation. It is therefore likely that MDM2, which is known to be modified by ubiquitination, SUMOylation and multi-site phosphorylation, may itself be a target for stress signalling (SUMO is small ubiquitin-related modifier-1). In the present study we show that, like p53, the MDM2 protein is a substrate for phosphorylation by the protein kinase CK2 (CK2) in vitro. CK2 phosphorylates a single major site, Ser267, which lies within the central acidic domain of MDM2. Fractionation of cellular extracts revealed the presence of a single Ser267 protein kinase which co-purified with CK2 on ion-exchange chromatography and, like CK2, was subject to inhibition by micromolar concentrations of the CK2-specific inhibitor 5,6-dichlororibofuranosylbenzimidazole. Radiolabelling of cells expressing tagged recombinant wild-type MDM2 or a S267A (Ser267 → Ala) mutant, followed by phosphopeptide analysis, confirmed that Ser267 is a cellular target for phosphorylation. Ser267 mutants are still able to direct the degradation of p53, but in a slightly reduced capacity. These data highlight a potential route by which one of several physiological modifications occurring within the central acidic domain of the MDM2 protein can occur.

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Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b01767 ◽

2016 ◽

Vol 59 (10) ◽

pp. 4526-4538 ◽

Cited By ~ 14

Author(s):

Simona Daniele ◽

Valeria La Pietra ◽

Elisabetta Barresi ◽

Salvatore Di Maro ◽

Eleonora Da Pozzo ◽

...

Keyword(s):

Lead Optimization ◽

Translocator Protein ◽

Double Minute ◽

Dual Inhibitors ◽

Murine Double Minute

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MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892814666191022163540 ◽

2020 ◽

Vol 14 (4) ◽

pp. 324-369 ◽

Cited By ~ 2

Author(s):

Rafał Rusiecki ◽

Jakub Witkowski ◽

Joanna Jaszczewska-Adamczak

Keyword(s):

Therapeutic Potential ◽

Research Work ◽

Academic Research ◽

Tumor Suppressor P53 ◽

Research Groups ◽

Current State ◽

Mouse Double Minute ◽

Patent Review ◽

Main Emphasis ◽

Double Minute

Background: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. Objective: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. Methods: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. Results: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. Conclusion: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

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MDM2 Amplified Sarcomas: A Literature Review

Diagnostics ◽

10.3390/diagnostics11030496 ◽

2021 ◽

Vol 11 (3) ◽

pp. 496

Author(s):

Raf Sciot

Keyword(s):

Suppressor Gene ◽

Negative Regulator ◽

Low Grade ◽

P53 Mutations ◽

Lipomatous Tumor ◽

Double Minute ◽

Genetic Features ◽

Murine Double Minute ◽

Well Differentiated ◽

Mdm2 Amplification

Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the best documented negative regulator of p53. Mutations of the tumor suppressor gene p53 represent the most frequent genetic change in human cancers. By overexpressing MDM2, cancer cells have another means to block p53. The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma. The purpose of this review is to summarize the typical clinical, histopathological, immunohistochemical, and genetic features of these tumors.

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