Design and Synthesis of Novel Small Molecule Inhibitors Targeting Mutant p53 for Cancer Therapy

Emilia Pavkov^*
*Correspondence: Emilia Pavkov, Department of Medicine and Surgery, University of Parma, Parma, Italy, Email:

Introduction

Mutations in the p53 tumor suppressor gene are among the most common alterations found in human cancers, with approximately 50% of all tumors carrying p53 mutations. The p53 protein plays a crucial role in maintaining cellular integrity by regulating processes such as DNA repair, cell cycle progression and apoptosis in response to cellular stress. Loss of p53 function, or the acquisition of gain-of-function mutations that alter its normal activity, leads to uncontrolled cell proliferation, resistance to apoptosis and increased genomic instability all hallmarks of cancer. While the wild-type p53 protein can activate a variety of tumor-suppressive mechanisms, mutant p53 proteins often exhibit aberrant activity that not only compromises these protective functions but can also promote oncogenic processes. In particular, mutant p53 has been shown to gain novel oncogenic properties, such as promoting cell migration, invasion and resistance to conventional chemotherapies. Despite significant advances in drug discovery, targeting p53 mutations has proven to be a formidable challenge due to the protein's intricate structure and the diverse nature of its mutations.. These inhibitors hold the potential to not only restore the tumor-suppressive functions of p53 but also reduce the gain-of-function oncogenic effects associated with mutant p53, offering a novel strategy for cancer therapy [1].

Description

The tumor suppressor gene p53 is one of the most critical genes in the regulation of cell growth and genomic stability. Its role in maintaining cellular integrity has made it a focal point in cancer research, as mutations in this gene are implicated in a broad array of human cancers. Approximately half of all cancers carry mutations in p53, making it the most frequently mutated gene in cancer. Under normal circumstances, p53 is a transcription factor that regulates a wide range of cellular processes, including cell cycle arrest, DNA repair, apoptosis and senescence, in response to cellular stress. This function is primarily aimed at preventing the propagation of damaged cells that could lead to tumorigenesis. In its wild-type form, p53 acts as a guardian of the genome, ensuring that cells with damaged DNA either repair the damage or undergo programmed cell death to prevent the accumulation of further mutations. However, mutations in the TP53 gene often lead to the production of a dysfunctional protein that loses its tumor-suppressive activities. These mutations are not only associated with the loss of normal p53 function but also with the acquisition of Gain-Of-Function (GOF) properties that contribute to cancer progression. The p53 protein is composed of several functional domains, including a DNA-binding domain, a tetramerization domain and a regulatory domain. Mutations in the TP53 gene can occur in any of these regions, with the majority of cancer-associated mutations being found within the DNA-binding domain. These mutations disrupt the proteinâ??s ability to bind to DNA and activate its target genes, thereby impairing its tumor-suppressive functions. In addition to these loss-of-function mutations, some p53 mutations can result in a conformational change that enables the mutant protein to acquire new, oncogenic properties [2].

Given the central role of p53 in cancer, targeting mutant p53 has become a highly attractive strategy for cancer therapy. The challenge, however, lies in the complexity of targeting this protein, particularly since p53 is a transcription factor with a highly dynamic and flexible structure. Moreover, because p53 mutations are diverse, with over 70,000 different variants cataloged in various databases, designing one-size-fits-all therapies for mutant p53 is challenging. Each mutant form of p53 exhibits a unique set of structural and functional alterations, meaning that a strategy effective for one mutant variant may not be effective for others. Despite these challenges, significant progress has been made in the development of small molecule inhibitors aimed at targeting mutant p53. These inhibitors can be broadly categorized into two main approaches: restoring the function of mutant p53 and inhibiting the GOF properties of the mutant protein. The first approach involves developing small molecules that can stabilize the mutant p53 protein in its native, wild-type conformation, thus restoring its tumor-suppressive activity. These compounds are often referred to as p53-reactivating agents. The second approach involves designing molecules that specifically inhibit the gain-of-function activities of mutant p53; preventing the protein from interacting with its oncogenic partners and blocking its pro-tumorigenic effects [3].

Several strategies have been explored for designing small molecules that can either restore normal p53 function or selectively inhibit the mutant protein. One such strategy focuses on small molecules that bind directly to the DNA-binding domain of mutant p53, stabilizing its conformation and enabling it to regain its ability to bind DNA and activate transcription of tumor-suppressive genes. PRIMA-1 works by covalently modifying the mutant p53 protein, restoring its wild-type conformation and allowing it to resume its normal function in controlling cell cycle progression and apoptosis. In clinical trials, APR-246 has demonstrated the ability to enhance the effectiveness of chemotherapy and reduce tumor growth in patients with p53 mutations. These compounds are designed to prevent the mutant protein from interacting with other cellular proteins that contribute to cancer progression. For example, small molecules that disrupt the interaction between mutant p53 and other transcription factors or signaling molecules may block the oncogenic effects of the mutant protein. One such compound is the small molecule inhibitor, MIRA-1, which prevents the binding of mutant p53 to the co-activator protein p300. This interaction is thought to be critical for the ability of mutant p53 to drive transcription of pro-survival and metastasis-promoting genes [4].

A third approach for targeting mutant p53 involves using chemical screens to identify small molecules that specifically bind to the p53 protein, stabilizing it in its wild-type conformation or selectively inhibiting its GOF activities. High-throughput screening methods have been used to identify compounds that can either restore the normal function of mutant p53 or selectively inhibit its oncogenic properties. Although the development of small molecule inhibitors targeting mutant p53 holds great promise for cancer therapy, there are several challenges that must be overcome before these drugs can be widely used in clinical practice. One major challenge is the heterogeneity of p53 mutations. This diversity makes it difficult to design a single small molecule that can target all forms of mutant p53. Moreover, some mutant forms of p53 may exhibit resistance to certain inhibitors, requiring the development of personalized treatment strategies. Another challenge is the potential for off-target effects, as the p53 protein is involved in numerous cellular processes. Targeting mutant p53 without affecting other critical cellular pathways requires a delicate balance and any inadvertent interference with normal cellular functions could lead to unintended side effects [5].

Conclusion

Despite these challenges, the development of small molecule inhibitors targeting mutant p53 represents an exciting and promising area of cancer research. As our understanding of the structure and function of p53 continues to grow and as new technologies in drug discovery and design emerge, the prospects for developing effective therapies targeting mutant p53 are improving. The potential for these therapies to restore normal p53 function or block the GOF properties of mutant p53 offers a novel and much-needed approach to cancer treatment. Given the high prevalence of p53 mutations in cancer, the successful development of these inhibitors could have a profound impact on the treatment of a wide range of cancers, ultimately improving survival rates and quality of life for patients. Therefore, ongoing efforts in this field are likely to pave the way for new and more effective cancer therapies in the coming years, offering hope to those whose cancers are driven by p53 mutations.

Acknowledgment

None.

Conflict of Interest

None.

References

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