Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6.

PURPOSE: Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and have achieved inspiring curative effects. But some discoveries have indicated that CDK 4/6 are not the requisite factors in some cell types because CDK2 partly compensates for the inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 inhibitors for significantly enhancing their potency. This study aims to explore the mechanism of the binding of CDK2/4/6 kinases and their inhibitors to design novel CDK2/4/6 inhibitors for significantly enhancing their potency in different kinds of cancers. MATERIALS AND METHODS: A series of 72 disparately functionalized 4-substituted N-phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 and CDK6 were collected to apply to this research. The total set of these derivatives was divided into a training set (54 compounds) and a test set (18 compounds). The derivatives were constructed through the sketch molecule module in SYBYL 6.9 software. A Powell gradient algorithm and Tripos force field were used to calculate the minimal structural energy and the minimized structure was used as the initial conformation for molecular docking. By the means of 3D-QSAR models, partial least squares (PLS) analysis, molecular dynamics (MD) simulations and binding free energy calculations, we can find the relationship between structure and biological activity. RESULTS: In this study, we used molecular docking, 3D-QSAR and molecular dynamics simulation methods to comprehensively analyze the interaction and structure-activity relationships of 72 new CDK2/4/6 inhibitors. We used detailed statistical data to reasonably verify the constructed 3D-QSAR models for three receptors (q2 of CDK2 = 0.714, R2pred = 0.764, q2 = 0.815; R2pred of CDK4 = 0.681, q2 = 0.757; R2pred of CDK6 = 0.674). MD simulations and decomposition energy analysis validated the reasonability of the docking results and identified polar interactions as crucial factors that influence the different bioactivities of the studied inhibitors of CDK2/4/6 receptors, especially the electrostatic interactions of Lys33/35/43 and Asp145/158/163. The nonpolar interaction with Ile10/12/19 was also critical for the differing potencies of the CDK2/4/6 inhibitors. We concluded that the following probably enhanced the bioactivity against CDK2/4/6 kinases: (1) electronegative groups at the N1-position and electropositive and moderate-sized groups at ring E; (2) electrogroups featured at R2; (3) carbon atoms at the X-position or ring C replaced by a benzene ring; and (4) an electrogroup as R4. CONCLUSION: Previous studies, to our knowledge, only utilized a single approach of 3D-QSAR and did not integrate this method with other sophisticated techniques such as molecular dynamics simulations to discover new potential inhibitors of CDK2, CDK4, or CDK6. So we applied the intergenerational technology, such as 3D-QSAR technology, molecular docking simulation techniques, molecular dynamics simulations and MMPBSA19/MMGBSA20-binding free energy calculations to statistically explore the correlations between the structure with biological activities. The constructed 3D-QSAR models of the three receptors were reasonable and confirmed by the excellent statistical data. We hope the results obtained from this work will provide some useful references for the development of novel CDK2/4/6 inhibitors.

Association between PT, PT-INR, and in-hospital mortality in critically ill patients with tumors: A retrospective cohort study.

Objectives: Prothrombin time (PT) and PT-INR are independent predictors of mortality in patients with cancer. The PT and PT-INR of cancer patients are independent predictive variables of mortality. However, whether the PT or PT-INR is related to in-hospital mortality in severely ill patients with tumors remains unknown. Design: This was a case-control study based on a multicenter public database. Settings: This study is a secondary analysis of data extracted from 2014 to 2015 from the Electronic Intensive Care Unit Collaborative Research Database. Participants: The data relevant to seriously ill patients with tumors were obtained from 208 hospitals spread throughout the USA. This research included a total of 200,859 participants. After the samples were screened for patients with combination malignancies and prolonged PT-INR or PT, the remaining 1745 and 1764 participants, respectively, were included in the final data analysis. Primary and secondary outcome measures: The key evaluation methodology was the PT count and PT-INR, and the main outcome was the in-hospital mortality rate. Results: After controlling for confounding variables, we found a curvilinear connection between PT-INR and in-hospital mortality (p < 0.001), and the inflection point was 2.5. When PT-INR was less than 2.5, an increase in PT-INR was positively associated with in-hospital mortality (OR 1.62, 95% CI 1.24 to 2.13), whereas when PT-INR was greater than 2.5, in-hospital mortality was relatively stable and higher than the baseline before the inflection point. Similarly, our study indicated that the PT exhibited a curvilinear connection with in-hospital mortality. On the left side of the inflection point (PT <22), a rise in the PT was positively linked with in-hospital mortality (OR 1.08, 95% CI 1.04 to 1.13, p < 0.001). On the right side of the inflection point, the baseline PT was above 22, and the in-hospital mortality was stable and higher than the PT count in the prior range (OR 1.01, 95% CI 0.97 to 1.04, 0.7056). Conclusion: Our findings revealed that there is a curved rather than a linear link between the PT or PT-INR and in-hospital mortality in critically ill cancer patients. When these two laboratory results are below the inflection point, comprehensive therapy should be employed to reduce the count; when these two laboratory results are above the inflection point, every effort should be made to reduce the numerical value to a value below the inflection point.

Subdivision of de-novo metastatic nasopharyngeal carcinoma based on tumor burden and pretreatment EBV DNA for therapeutic guidance of locoregional radiotherapy.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy predominantly associated with infection by the Epstein-Barr virus (EBV). Approximately 12,900 new cases of NPC occur each year, with more than 70% of cases occurring in the east and southeast Asia. NPC is different from ordinary head and neck squamous cell carcinoma due to its particular biological properties and it is highly sensitive to radiotherapy. With the development of RT technology, the 3-year local control rate and survival rates of non-metastatic NPC reached 80-90% in the intensity-modulated RT (IMRT) era. However, whether distant metastatic NPC (de novo mNPC, dmNPC) should receive locoregional RT (LRRT) needs to be clarified. RESULTS: Multivariate analysis identified three independent prognostic factors: Epstein-Barr virus (EBV) DNA, number of metastatic lesions, and number of metastatic organs. Through these factors, all patients were successfully divided into 3 subgroups: low-risk (single metastatic organ, EBV DNA ≤ 25,000 copies/ml, and ≤ 5 metastatic lesions), intermediate-risk (single metastatic organ, EBV DNA > 25,000 copies/ml, and ≤ 5 metastatic lesions), and high-risk (multiple metastatic organs or > 5 metastatic lesions or both). By comparing LRRT and non-LRRT groups, statistical differences were found in OS in the low-risk and intermediate-risk subgroups (p = 0.039 and p = 0.010, respectively) but no significant difference was found in OS in the high-risk subgroup (p = 0.076). Further multivariate analysis of different risk stratifications revealed that LRRT can improve OS of low- and intermediate-risk subgroups. CONCLUSIONS: The risk stratification of dmNPC may be used as a new prognostic factor to help clinicians organize individualized LRRT treatment to improve the survival outcomes of dmNPC patients.