Discovery Of Novel Inhibitors Of The Lipid Kinases PI3Kδ And PfPI4K

In this thesis,we described our efforts toward the discovery of novel selective inhibitors targeting Phosphoinositide 3-kinase δ(PI3K8)and Plasmodium falciparum Phosphatidylinositol 4-kinase(PfPI4K).Studies have shown that lipid kinase PI3K8 is a promising drug target for B-cell tumors,inflammation and autoimmune diseases.Although PI3Kδ inhibitor Idelalisib(CAL-101)has been launched for B-cell related cancer,a pattern of unpredictable toxicity has led to a black box warning,which is limiting its current use as immunomodulating agent.In addition,there is no PI3Kδ inhibitor approved for nononcology diseases.Therefore,it’s urgent to discover novel PI3K8 inhibitor with fewer side effects.Starting from reported multi-target PI3K inhibitor,we discovered the lead compound CHMFL-PI3Kδ-317(compound 22h)via computer-aided design and structural modifications.22h can significantly inhibit the activity of PI3Kδ and its downstream signaling pathway.And 22h achieves high selectivity over other PI3K isoforms and kinase profile including 468 kinases/mutants.In addition,22h can dosedependently inhibit the tumor growth in the MOLM14 cell-inoculated xenograft mouse model.The study provided a valuable tool compound for further biological and pathological investigation on PI3Kδ.In view of limited safety window of 22h,in order to discover more druggable PI3Kδ inhibitor and expand the structure diversity,we also make efforts on propellershape quinazolinone PI3Kδ inhibitors.Based on the fragment hybridization strategy,through computer-aided design and structural optimizations,we explored the fragments bound to the PI3Kδ hydrophobic region Ⅱ and affinity pocket.The lead compound IHMT-PI3Kδ-372((S)-35e)shows high potency and high selectivity in vitro,and also exhibits high selectivity among the kinase family.In addition,(S)-35e did not show significant inhibitory activity against multiple subtypes of CYP450 and hERG,which indicates that the compound may not cause drug-drug interaction and potential cardiotoxicity.We also evaluated its efficacy in chronic obstructive pulmonary disease(COPD)model in rats via inhaled administration.(S)-35e dose-dependently improves the lung function of COPD animal models.Preliminary safety evaluation,pharmacokinetic properties and pharmacological studies make(S)-35e a promising lead compound and provide the new insight for discovery of COPD agents.Malaria is a major public health problem worldwide.According to the World Malaria Report released by the World Health Organization every year,there are more than 200 million infections and more than 400,000 deaths caused by malaria each year.Recent years,malaria resistant to artemisinin has been reported.To achieve the goal of eliminating malaria globally still faces many challenges,so there is an urgent need for new antimalarial agents with novel mechanism.Current studies have shown that inhibiting Plasmodium PI4K kinasecan inhibit multiple stages of the malaria life cycle.PfPI4K,which belongs to the lipid kinase family,is expected to become a new target for antimalarial drug discovery.Based on the hit compound screening from the compound library,through computer-aided drug design and medicinal chemistry strategy,we discovered the bipyridine lead compound CHMFL-PI4K-127(55g).55g has strong inhibitory activity against PfPI4K,and has achieved high selectivity over host kinase.The compound also displays anti-proliferative aitivity against drugresistant malaria.In addition,55g shows good pharmacokinetic properties in rats and mice.In rodent malaria model,55g displays the effect of treating and preventing malaria,which cannot be achieved by most other antimalarial drugs including artemisinin.The study results make it a promising candidate for anti-malaria.