Nicotinonitrile-derived apoptotic inducers: Design, synthesis, X-ray crystal structure and Pim kinase inhibition.

Although a plethora of targeted anticancer small molecule drugs became available, the low response rate and drug resistance imply the continuous need for expanding the anticancer chemical space. In this study, a novel series of nicotinonitrile derivatives was designed, synthesized and evaluated for cytotoxic activities in HepG2 and MCF-7 cells. All derivatives showed high to moderate cytotoxic activity against both cell lines, with cell-type and chemotype-dependent cytotoxic potential. The normal HEK-293 T cells were ca. 50-fold less susceptible to the cytotoxic effect of the inhibitors. The in vitro enzyme inhibitory activity of selected active cytotoxic derivatives 8c, 8e, 9a, 9e and 12 showed that they have sub- to one digit micromolar 50 % inhibitory concentration (IC50) against the three Pim kinase isoforms, with 8e being the most potent (IC50 ≤ 0.28 µM against three Pim kinases), comparable to the pan kinase inhibitor, Staurosporine. In HepG2, 8e induced cell cycle arrest at the G2/M phase. Apoptotic mechanistic studies with 8c and 8e in HepG2 cells, indicated a significant upregulation in both P53 and caspase-3 relative gene expression, as well as increased Bax/Bcl-2 protein expression level. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of 8e to Pim-1 kinase; exploiting a negative electrostatic potential surface interaction with the added dimethyl amino group in the new compounds. Moreover, in silico ADME profile prediction indicated that all compounds are orally bioavailable and most of them can penetrate the blood-brain barrier. This study presents novel nicotinonitrile derivatives as auspicious hits for further optimization as antiproliferative agents against liver cancer cells and promising pan Pim kinase inhibitors at submicromolar concentrations.

Diagnosing 'transition' to secondary progressive multiple sclerosis (SPMS): A step-by-step approach for clinicians.

Upon the approval of disease-modifying therapies (DMTs) for patients with active secondary progressive phase of multiple sclerosis (SPMS), there became an emerging need to prospectively predict and diagnose patients transitioning from the relapsing-remitting to the secondary progressive phase of MS. Whilst several research articles handle the challenges for diagnosing this stage of the disease, a clear step-by-step diagnostic approach remains elusive. This review aims at providing a step-by-step diagnostic approach to patients within 'transitioning' MS based on the currently available research findings and to summarize the gaps in the diagnostic approach and the recommendations for future research in this area of practice.