scholarly journals Structural and Drug Targeting Insights on Mutant p53

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3344
Author(s):  
Ana Sara Gomes ◽  
Helena Ramos ◽  
Alberto Inga ◽  
Emília Sousa ◽  
Lucília Saraiva
Keyword(s):  
Small Molecules ◽  
Drug Targeting ◽  
Normal Function ◽  
Structure Stability ◽  
Mutant P53 ◽  
Structural Studies ◽  
Wild Type ◽  
Tumor Onset ◽  
Long Time ◽  
Stability Dynamics

p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.

scholarly journals Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1637
Author(s):  
Solida Long ◽  
Joana B. Loureiro ◽  
Carla Carvalho ◽  
Luís Gales ◽  
Lucília Saraiva ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Small Molecules ◽  
Tumor Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Naturally Occurring ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Amino Derivatives ◽  
Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

Small Molecules Targeting Mutant P53: A Promising Approach for Cancer Treatment

2020 ◽  
Vol 26 (41) ◽  
pp. 7323-7336 ◽  
Author(s):  
Elizabeth A. Lopes ◽  
Sara Gomes ◽  
Lucília Saraiva ◽  
Maria M.M. Santos
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Colorectal Cancers ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
Tumor Types ◽  
Mutant Forms

: More than half of all human tumors express mutant forms of p53, with the ovary, lung, pancreas, and colorectal cancers among the tumor types that display the highest prevalence of p53 mutations. In addition, the expression of mutant forms of p53 in tumors is associated with poor prognosis due to increased chemoresistance and invasiveness. Therefore, the pharmacological restoration of wild-type-like activity to mutant p53 arises as a promising therapeutic strategy against cancer. This review is focused on the most relevant mutant p53 small molecule reactivators described to date. Despite some of them have entered into clinical trials, none has reached the clinic, which emphasizes that new pharmacological alternatives, particularly with higher selectivity and lower adverse toxic side effects, are still required.

scholarly journals Function of a Mycobacterial Major Facilitator Superfamily Pump Requires a Membrane-Associated Lipoprotein

2007 ◽  
Vol 190 (5) ◽  
pp. 1783-1791 ◽  
Author(s):  
Mary F. Farrow ◽  
Eric J. Rubin
Keyword(s):  
Drug Resistance ◽  
Cell Surface ◽  
Small Molecules ◽  
Ethidium Bromide ◽  
Mycobacterium Smegmatis ◽  
Normal Function ◽  
Cell Wall Composition ◽  
Major Facilitator Superfamily ◽  
Wild Type ◽  
Major Facilitator

ABSTRACT The lprG-Rv1410c operon is critical for the survival of Mycobacterium tuberculosis during infection, but very little is known about the functions of its proteins. LprG is a lipoprotein, and Rv1410c encodes the major facilitator superfamily small molecule transporter P55. P55 likely exports small molecules outside of the bacterial cell, but the function of LprG is unclear. A deletion of the homologous operon in Mycobacterium smegmatis is more susceptible to ethidium bromide, and drug resistance is restored by the intact operon from M. tuberculosis. The multidrug resistance pump inhibitor reserpine inhibits resistance to ethidium bromide in both wild-type M. smegmatis and the complemented mutant, suggesting that P55-mediated transport is responsible for drug resistance and that ethidium bromide is a novel substrate for P55. In addition to hypersensitivity to ethidium bromide, cells that lack the lprG-Rv1410c operon display abnormal colony morphology and are defective for sliding motility, properties that suggest an alteration of cell wall composition. Strikingly, both ethidium bromide transport and normal cell surface properties require functional P55 and LprG, as neither alone is sufficient to restore function to the deletion mutant. Thus, P55 requires the cell surface lipoprotein for normal function.

scholarly journals Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 98
Author(s):  
Paola Menichini ◽  
Paola Monti ◽  
Andrea Speciale ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cell Metabolism ◽  
Therapy Response ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Lower Percentage ◽  
Mutant P53 ◽  
Wild Type ◽  
Antitumor Effects ◽  
Tp53 Tumor Suppressor Gene

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

scholarly journals Suberoylanilide hydroxamic acid enhances the radiosensitivity of lung cancer cells through acetylated wild-type and mutant p53-dependent modulation of mitochondrial apoptosis

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098154
Author(s):  
Kan Wu ◽  
Xueqin Chen ◽  
Xufeng Chen ◽  
Shirong Zhang ◽  
Yasi Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Hydroxamic Acid ◽  
Site Directed Mutagenesis ◽  
Lung Cancer Cells ◽  
Mutant P53 ◽  
Suberoylanilide Hydroxamic Acid ◽  
Mitochondrial Apoptosis ◽  
Wild Type ◽  
Clonogenic Cell

Objective Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has shown potential as a candidate radiosensitizer for many types of cancers. This study aimed to explore the radiosensitization mechanism of SAHA in lung cancer cells. Methods Mutations in p53 were generated by site-directed mutagenesis using polymerase chain reaction. Transfection was performed to generate H1299 cells carrying wild-type or mutant p53. The radiosensitizing enhancement ratio was determined by clonogenic assays. Mitochondrial apoptosis was detected using JC-1 staining and flow cytometry analysis. Results Our results showed that SAHA induced radiosensitization in H1299 cells expressing wild-type p53, p53R175H or p53P223L, but this enhanced clonogenic cell death was not observed in parental H1299 (p53-null) cells or H1299 cells expressing p53 with K120R, A161T and V274R mutations. In SAHA-sensitized cells, mitochondrial apoptosis was induced following exposure to irradiation. Additionally, we observed that a secondary mutation at K120 (K120R) could eliminate p53-mediated radiosensitization and mitochondrial apoptosis. Conclusions The results of this study suggest that wild-type and specific mutant forms of p53 mediate SAHA-induced radiosensitization by regulating mitochondrial apoptosis, and the stabilization of K120 acetylation by SAHA is the molecular basis contributing to radiosensitization in lung cancer cells.

scholarly journals Expression Level of Mature miR172 in Wild Type and StSUT4-Silenced Plants of Solanum tuberosum Is Sucrose-Dependent

2021 ◽  
Vol 22 (3) ◽  
pp. 1455
Author(s):  
Varsha Garg ◽  
Aleksandra Hackel ◽  
Christina Kühn
Keyword(s):  
Solanum Tuberosum ◽  
Wild Type ◽  
Potato Plants ◽  
Mature Leaves ◽  
In Vitro Plantlets ◽  
Long Time ◽  
Short Time ◽  
Cut Leaves

In potato plants, the phloem-mobile miR172 is involved in the sugar-dependent transmission of flower and tuber inducing signal transduction pathways and a clear link between solute transport and the induction of flowering and tuberization was demonstrated. The sucrose transporter StSUT4 seems to play an important role in the photoperiod-dependent triggering of both developmental processes, flowering and tuberization, and the phenotype of StSUT4-inhibited potato plants is reminiscent to miR172 overexpressing plants. The first aim of this study was the determination of the level of miR172 in sink and source leaves of StSUT4-silenced as well as StSUT4-overexpressing plants in comparison to Solanum tuberosum ssp. Andigena wild type plants. The second aim was to investigate the effect of sugars on the level of miRNA172 in whole cut leaves, as well as in whole in vitro plantlets that were supplemented with exogenous sugars. Experiments clearly show a sucrose-dependent induction of the level of mature miR172 in short time as well as long time experiments. A sucrose-dependent accumulation of miR172 was also measured in mature leaves of StSUT4-silenced plants where sucrose export is delayed and sucrose accumulates at the end of the light period.

scholarly journals Role of SpoVA Proteins in Release of Dipicolinic Acid during Germination of Bacillus subtilis Spores Triggered by Dodecylamine or Lysozyme

2006 ◽  
Vol 189 (5) ◽  
pp. 1565-1572 ◽  
Author(s):  
Venkata Ramana Vepachedu ◽  
Peter Setlow
Keyword(s):  
Bacillus Subtilis ◽  
Small Molecules ◽  
Spore Germination ◽  
Dipicolinic Acid ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Ph Optimum ◽  
Inner Membrane ◽  
Temperature Sensitive Mutants

ABSTRACT The release of dipicolinic acid (DPA) during the germination of Bacillus subtilis spores by the cationic surfactant dodecylamine exhibited a pH optimum of ∼9 and a temperature optimum of 60°C. DPA release during dodecylamine germination of B. subtilis spores with fourfold-elevated levels of the SpoVA proteins that have been suggested to be involved in the release of DPA during nutrient germination was about fourfold faster than DPA release during dodecylamine germination of wild-type spores and was inhibited by HgCl2. Spores carrying temperature-sensitive mutants in the spoVA operon were also temperature sensitive in DPA release during dodecylamine germination as well as in lysozyme germination of decoated spores. In addition to DPA, dodecylamine triggered the release of amounts of Ca2+ almost equivalent to those of DPA, and at least one other abundant spore small molecule, glutamic acid, was released in parallel with Ca2+ and DPA. These data indicate that (i) dodecylamine triggers spore germination by opening a channel in the inner membrane for Ca2+-DPA and other small molecules, (ii) this channel is composed at least in part of proteins, and (iii) SpoVA proteins are involved in the release of Ca2+-DPA and other small molecules during spore germination, perhaps by being a part of a channel in the spore's inner membrane.

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