Their efforts identified a number of novel compounds with appreciable in vitro activity and selectivity, such as compound 9. more extensive research is needed Cevipabulin (TTI-237) to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment. strong class=”kwd-title” Keywords: proteinCprotein interactions, cervical cancer, HPV E6, small molecules, peptides, drug discovery, targeted therapy 1. Background Cervical cancer (CC) is an oncologic disease of the uterine cervix caused by an oncogenic virus called human papillomavirus (HPV). According to WHO estimates, about 600,000 new cases are recorded annually, and more than half of these people die [1,2]. Finding ways to reduce this huge burden of cervical cancer is therefore imperative. The advent of anti-HPV prophylactic vaccines and their continued use will help with reducing the number of cases significantly in the future. For this approach to be effective, the vaccine must be administered pre-infection, and the rates of vaccine uptake need to be high. Unfortunately, vaccine coverage in both developed and developing countries has been suboptimal, with less than 50% coverage in most regions across the globe [3,4]. If these challenges persist, new cases of cervical cancer will remain significant, and the need for more effective clinical management of the disease will continue. Generally, when the disease is caught early, when surgery and/or radiotherapy can be used, the clinical outcomes are good with cure rates between 80% and 90% [5]. For stages IIB to IVA, a multidisciplinary approach that usually involves chemoradiation is employed. For patients with stage IVB or metastatic disease, systemic therapy is the standard of care. Even though recurrence is only between 10% and 20% for early stage CC, it can be as high as 50% to 70% for advanced disease within 2 years of completing treatment [6,7]. Once the cancer recurs, the 5-year survival rate is 5%. Patients in this recurrent, persistent, and metastatic category, therefore, represent a current clinical challenge and need that has not been met [7,8,9,10,11,12]. The standard of care (SOC) for patients with advanced CC is systemic therapy, and cisplatin has been the cornerstone of this treatment since its introduction in the early 1980s [8,9,10,11]. Given the limited efficacy in this patient subgroup, improving survival has always been an area of interest. It was initially observed that increasing the cisplatin dosage enhanced response rates (RRs) yet did very little to improve overall survival (OS) [8,9,11]. Furthermore, at these higher doses of cisplatin, toxicity was often intolerable. Other platinum-based agents, such as carboplatin, were less toxic but had lower response rates. Another issue that arose was platinum resistance [8,11]. To overcome some of these problems, several combinations of chemotherapeutics, where cisplatin-containing agents were paired with agents such as topotecan, gemcitabine, vinorelbine, were evaluated in various Gynecologic Oncology Group (GOG) trials. Of these many studies, GOG-169 in 1999 showed that the addition of cisplatin to paclitaxel doubled the RR and progression-free survival (PFS). A decade and half later, the GOG-240 trial successfully tested the addition of bevacizumab to the cisplatinCpaclitaxel doublet, and this combination became the first combination study to demonstrate an improvement in OS (added 3 months) without a decline in quality of life. In 2014, this chemobiologic cocktail became the first-line choice of treatment for patients with advanced disease [8,9,10,11,13]. Because bevacizumab inhibits a specific target called VEGF, the study has a renewed interest in the idea that other targeted agents could offer additional gains in survival. Accordingly, a number of nonangiogenic cellular effectors were targeted in various.One of these viral proteins is E6, which affects an oncogenic phenotype through proteinCprotein interactions (PPIs). knowledge and understanding of specific Cevipabulin (TTI-237) E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment. strong class=”kwd-title” Keywords: proteinCprotein interactions, cervical cancer, HPV E6, small molecules, peptides, drug discovery, targeted therapy 1. Background Cervical cancer (CC) is an oncologic disease of the uterine cervix caused by an oncogenic virus called human papillomavirus (HPV). According to WHO estimates, about 600,000 new cases are recorded annually, and more than half of these people die [1,2]. Finding ways to reduce this huge burden of cervical cancer is therefore imperative. The Cevipabulin (TTI-237) advent of anti-HPV prophylactic vaccines and their continued use will help with reducing the number of cases significantly in the future. For this approach to be effective, the vaccine must be administered pre-infection, and the rates of vaccine uptake need to be high. Unfortunately, vaccine coverage in both developed and developing countries has been suboptimal, with less than 50% coverage in most regions across the globe [3,4]. If these challenges persist, new cases of cervical cancer will remain significant, and the need for more effective clinical management of the disease will continue. Generally, when the disease is caught early, when surgery and/or radiotherapy can be used, the clinical outcomes are good with cure rates between 80% and 90% [5]. For stages IIB to IVA, a multidisciplinary approach that usually involves chemoradiation is employed. For patients with stage IVB or metastatic disease, systemic therapy is the standard of care. Even though recurrence is only between 10% and 20% for early stage CC, it can be as high as 50% to 70% for advanced disease within 2 years of completing treatment [6,7]. Once the malignancy recurs, the 5-12 months survival rate is definitely 5%. Patients with this recurrent, prolonged, and metastatic category, consequently, represent a present clinical challenge and need that has not been met [7,8,9,10,11,12]. The standard of care and attention (SOC) for individuals with advanced CC is definitely systemic therapy, and cisplatin has been the cornerstone of this treatment since its intro in the early 1980s [8,9,10,11]. Given the limited effectiveness in this patient subgroup, improving survival has always been an area of interest. It was in the beginning observed that increasing the cisplatin dose enhanced response rates (RRs) yet did very little to improve overall survival (OS) [8,9,11]. Furthermore, at these higher doses of cisplatin, toxicity was often intolerable. Additional platinum-based agents, such as carboplatin, were less harmful but experienced lower response rates. Another issue that arose was platinum resistance [8,11]. To conquer Cevipabulin (TTI-237) some of these problems, several mixtures of chemotherapeutics, where cisplatin-containing providers were paired with providers such as topotecan, gemcitabine, vinorelbine, were evaluated in various Gynecologic Oncology Group (GOG) tests. Of these many studies, GOG-169 in 1999 showed the addition of cisplatin to paclitaxel doubled the RR and progression-free survival (PFS). A decade and half later on, the GOG-240 trial successfully tested the addition of bevacizumab to the cisplatinCpaclitaxel doublet, and Cevipabulin (TTI-237) this combination became the 1st combination study to demonstrate an improvement in OS (added 3 months) without a decrease in quality of life. In 2014, this chemobiologic cocktail became the first-line choice of treatment for individuals with advanced disease [8,9,10,11,13]. Because bevacizumab inhibits a specific target called VEGF, the study has a renewed desire for the idea that additional targeted agents could offer additional gains in survival. Accordingly, a number GPR44 of nonangiogenic cellular effectors were targeted in various clinical studies over the past few decades. Surprisingly, focusing on the proliferative and prosurvival pathways in CC has been mainly disappointing. Several EGFR inhibitors, including both monoclonal antibodies and small molecules, as well as mTOR analogues, have all failed to progress beyond phase III trials. Inhibitors of HDACs and PARP have also underperformed [9,10,11]. These findings and the fact that treatment regimens and OS have barely changed since the inception of cisplatin 4 decades ago spotlight at least two points: (i) there exists a significant lack of clinically efficacious and selective providers,.