merck p53 stapled peptide stapled peptides with in vivo activity - membrane-active-peptides meant to mimic a key helix in the p53 protein Merck p53 Stapled Peptide: A Novel Therapeutic Approach in Oncology

sj-peptides The development of innovative cancer therapies is a relentless pursuit in pharmaceutical research.Preliminary Results of the Stapled Peptide ALRN-6924, a ... Among the most promising avenues is the exploration of stapled peptides, a class of molecules designed to mimic natural protein structures while offering enhanced stability and therapeutic potential. A key focus in this area is the Merck p53 stapled peptide, which targets the intricate interaction between the p53 tumor suppressor protein and its negative regulators, MDM2 and MDMX. This interaction plays a critical role in controlling cell growth and preventing cancer development.The Stapled Peptide That Made It Furthest

The p53 protein is often referred to as the "guardian of the genome" due to its crucial role in maintaining genomic stability.作者：K Sharma·2020·被引用次数：18—To explore this concept, we targeted the design and synthesis ofstapled peptide inhibitors of the p53-MDM2 PPIwhich incorporated substituents ... It acts as a transcription factor that initiates cell cycle arrest, apoptosis, or senescence in response to DNA damage or other cellular stresses, thereby preventing the proliferation of damaged cells. In many cancers, the p53 pathway is inactivated, often through overexpression of MDM2 and MDMX, proteins that bind to p53 and promote its degradation作者：YS Chang·2013·被引用次数：812—We report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates thep53pathway in tumors in vitro and in vivo.. This prevents MDM2 from suppressing wild-type p53, allowing damaged cells to survive and proliferateStereoisomerism of stapled peptide inhibitors of the p53 ....

This is where stapled peptides come into play. These peptides are engineered with a chemical "staple" that locks them into a specific, biologically active conformation, typically an alpha-helical structure. This stabilization confers several advantages over traditional peptides, including increased resistance to enzymatic degradation and improved cell permeabilityThese cross-linked peptidomimetic macrocycles contain at least two modified amino acids that together form an intramolecular cross-link that stabilizes the .... The Merck p53 stapled peptide research, alongside other efforts in the field, aims to leverage these properties to develop drugs that can disrupt the p53-MDM2/MDMX interaction.

Stapled peptide drug development has shown significant promise.作者：K Hu·2021·被引用次数：2—The goal of this work is to develop astapled peptide-based radiotheranostic agentsfor PET-imaging guided radiotherapy of p53 mutant cancer. For instance, stapled peptides like ALRN-6924 are designed to be cell-penetrating stapled alpha-helical peptides that equipotently disrupt the interaction between the p53 tumor suppressor protein and its inhibitors. Research on stapled peptides has demonstrated their ability to reactivate p53 and inhibit cancer cell growth. Studies have explored various strategies, including the development of bicyclic stapled peptide p53-16, which exhibits enhanced alpha-helicity and proteolytic stability, leading to nanomolar binding affinity作者：S Crunkhorn·2013·被引用次数：10—The authors developed a stable hydrocarbon-stapledα-helicalpeptidetherapeutic, based on the biologically active α-helical conformation found ....

The design of these stapled peptides often involves mimicking key structural elements of the p53 protein itself2023年2月26日—Thep53/Mdm2 PPI represents a valuable opportunity to make cross-modality comparisons since both small molecule andstapled peptideantagonists .... One such approach involves creating a stapled peptide that is meant to mimic a key helix in the p53 protein, enabling it to bind to MDM2 and prevent the degradation of p53.Stapled peptides as scaffolds for developing radiotracers ... This strategy has led to the development of potent dual inhibitors of MDM2 and MDMX. For example, ATSP-7041 is a stapled alpha-helical peptide that effectively activates the p53 pathway in tumors.

The development of stapled peptides is not limited to small molecule inhibitors. Researchers are also exploring their application in more advanced therapeutic modalities. Stapled peptide-based radiotheranostic agents, such as those labeled with 64Cu, are being developed for PET-imaging guided radiotherapy of p53 mutant cancer. These agents can simultaneously diagnose and treat cancer by delivering therapeutic radiation to tumor sites. Further advancements include the creation of stapled peptide-based radiopharmaceuticals that have demonstrated effective inhibition of tumor growth, irrespective of p53 phenotypes.Stapled Peptide-based radiotheranostics agent targeting ...

The scientific community has made significant strides in understanding the structure-activity relationships of these molecules. For example, the structure of the stapled p53 peptide bound to Mdm2 has been elucidated, providing valuable insights for further drug design作者：K Ingelshed—We found that thep53activatingstapled peptideMDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibitedp53wild-type cancer cell growth in .... Research has also focused on optimizing the "stapling" process itself, with studies investigating optimal stapling of a helical peptide-foldamer hybrid and exploring different linker chemistries for double-click staples.We demonstrated thatbicyclic stapled peptide p53-16significantly improved α-helicity and proteolytic stability. Especially, p53-16 showed nanomolar binding ... The development of functionalized double strain-promoted stapled peptides and the investigation of peptide sequence variations for 'double-click' stapling are examples of ongoing efforts to refine these therapeutic agents.

The therapeutic potential of stapled peptides extends to various cancer types. These molecules have exhibited great potential as anti-cancer drugs.Cell-Permeable Peptide Inhibitors of the p53-hDM2 ... Their ability to disrupt the p53/MDM2 interaction is a promising strategy for developing novel therapeutic leads. Furthermore, the field is exploring advanced applications, such as design of stapled peptide-based PROTACs for MDM2/MDMX antagonism, highlighting the versatility of this therapeutic platform.

The ongoing research into Merck p53 stapled peptide and related compounds underscores the transformative potential of this technology作者：G Tiwari·2016—In order to inhibit the p53-MDM2 interaction, we have successfully designedstapled peptides(sMTide-02)1, 2. It is a potential lead compound for drug .... With continued innovation in stapled peptide drug development, these molecules are poised to play a significant role in the future of cancer therapy, offering new hope for patients with various malignancies. The exploration of stapled peptides continues to evolve, with new findings on how stapled peptides shapeshift to slip through cellular barriers and target disease-related proteins. The development of stapled peptides with in vivo activity is a critical step towards clinical translation, and compounds like stapled diurea-peptide 8 a are being investigated for their ability to restore the p53 signaling pathway. The potency of certain stapled peptides, such as Stapled peptide SP6, in inhibiting interactions is also a subject of active research, as is the development of stapled peptide inhibitors of the p53-MDM2 PPI. Ultimately, stapling peptides for inhibiting the p53/MDM2 interaction represents a significant advancement in targeted cancer therapeutics.