C-3-1

Latest studies confirmed that abnormal function of histone deacetylase (HDAC) plays a pivotal role in formation of tumors and is a potential therapeutic target for treating breast cancer. In this research, in-silico drug discovery approaches via quantitative structure activity relationship (QSAR) and molecular docking simulations were adapted to 43 compounds of indazole derivatives with HDAC inhibition for anticancer activity against breast cancer. The QSAR models were built from multiple linear regression (MLR), and models predictability was cross-validated by leave-one-out (LOO) method. Based on these results, compounds C32, C26 and C31 from model 3 showed superior inhibitory activity with pIC₅₀ of 9.30103, 9.1549 and 9.1549. We designed 10 novel compounds with molecular docking scores ranging from -7.9 to -9.3 kcal/mol. The molecular docking simulation results reveal that amino acid residues ILE1122 and PRO1123 play a significant role in bonding with 6CE6 protein. Furthermore, newly designed compounds P5, P2 and P7 with high docking scores of -9.3 kcal/mol, -8.9 kcal/mol and -8.8 kcal/mol than FDA-approved drug Raloxifene (-8.5 kcal/mol) and aid in establishment of potential drug candidate for HDAC inhibitors. The in-silico ADME functionality is used in the final phase to evaluate newly designed inhibitors as potential drug candidates. The results suggest that newly designed compounds P5, P2 and P7 can be used as a potential anti-breast cancer drug candidate.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with anti-infectives is the only effective treatment regime besides intensive care. In search for additional treatment options, we recently discovered the inhibition of the sphingosine 1-phosphate (S1P) lyase and subsequent activation of the S1P receptor type 3 (S1PR3) in pre-conditioning experiments as promising targets for sepsis prevention. Here, we demonstrate that treatment of septic mice with the direct S1P lyase inhibitor C31 or the S1PR3 agonist CYM5541 in the advanced phase of sepsis resulted in a significantly increased survival rate. A single dose of each compound led to a rapid decline of sepsis severity in treated mice and coincided with decreased cytokine release and increased lung barrier function with unaltered bacterial load. The survival benefit of both compounds was completely lost in S1PR3 deficient mice. Treatment of the murine macrophage cell line J774.1 with either C31 or CYM5541 resulted in decreased protein kinase B (Akt) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) phosphorylation without alteration of the mitogen-activated protein kinase (MAPK) p38 and p44/42 phosphorylation. Thus, activation of S1PR3 in the acute phase of sepsis by direct agonism or S1P lyase inhibition dampened Akt and JNK phosphorylation, resulting in decreased cytokine release, improved lung barrier stability, rapid decline of sepsis severity and better survival in mice.