Cunlong Zhang

Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors.

Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated. Among these compounds, compounds 5a and 5e exhibited high cytotoxicity against HepG-2 cells with IC₅₀ values at ∼2 μM. Further kinase assay study showed that compound 5a have good EGFR inhibitory activity and moderate VEGFR-2 and PDGFR inhibitory activities, while 5e have moderate EGFR inhibitory activity and slightly weaker VEGFR-2 and PDGFR inhibitory activities. Molecular docking analysis suggested that compound 5a more tightly interacts with EGFR and PDGFR than compound 5e. Our study discovered a novel series of benzimidazole derivatives as multi-target EGFR, VEGFR-2 and PDGFR kinases inhibitors.

Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors

Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition.

Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor treatment

Based on the roles of Raf1 and JNK1 in hepatocarcinoma development, scaffold-based drug design was employed to produce a series of compounds, which subsequently were synthesized and explored as potential dual inhibitors Raf1 and JNK1 kinases for anti-tumor treatment. The compound 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chloro-phenyl)urea (3d) showed 66%, 67% and 13% inhibition rate at 50 μM against Raf1, JNK1 and p38-alpha, respectively, but no effect on ERK1 and ERK2, and inhibited the expression of pERK1/2 markedly and HepG2 cells proliferation with IC(50) at 8.3 μM. Furthermore, 3d showed lower toxicity against normal liver cell-lines QSG7701 and HL7702. Molecular docking study further showed that 3d can fit into binding domain of JNK1 and Raf1. Our data suggested the activities of 3d were associated with dual inhibition of JNK1 and Raf1 kinases.

Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives.

A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC50 = 1.4 μM) compared with sorafenib (IC50 = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC50 = 22.6 μM).

Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites

Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, we generated and evaluated the distribution patterns of 442 NPLDs of 749 pre-2013 approved and 263 clinical trial small molecule drugs in the chemical space represented by the molecular scaffold and fingerprint trees of 137,836 non-redundant natural products. In the molecular scaffold trees, 62.7% approved and 37.4% clinical trial NPLDs congregate in 62 drug-productive scaffolds/scaffold-branches. In the molecular fingerprint tree, 82.5% approved and 63.0% clinical trial NPLDs are clustered in 60 drug-productive clusters (DCs) partly due to their preferential binding to 45 privileged target-site classes. The distribution patterns of the NPLDs are distinguished from those of the bioactive natural products. 11.7% of the NPLDs in these DCs have remote-similarity relationship with the nearest NPLD in their own DC. The majority of the new NPLDs emerge from preexisting DCs. The usefulness of the derived knowledge for NPLD discovery was demonstrated by the recognition of the new NPLDs of 2013–2014 approved drugs.

Selective VEGFR inhibitors for anticancer therapeutics in clinical use and clinical trials.

Angiogenesis and vasculogenesis, regulated by VEGF/VEGFR signaling pathways, play key roles in tumor growth and metastasis. Selective inhibition of VEGFR kinase has been explored as a highly successful clinical strategy in cancer treatment. A number of VEGFR inhibitors have been approved in clinical use and many more are in various stages of drug development. This paper reviews selective small-molecule VEGFR inhibitors in clinical uses and in clinical trials, with particular focus on in vitro, in vivo and clinical trial results of these inhibitors. The VEGF/VEGFR genes and signaling pathways involved in tumor angiogenesis, and the strategies for accessing and improving the therapeutic efficacy of VEGFR inhibitors are also discussed.

Multitarget inhibitors derived from crosstalk mechanism involving VEGFR2

Seven VEGFR small-molecule inhibitors have been approved by the US FDA as anticancer drugs, which confirms the therapeutic value of angiogenesis inhibitors. However, much more evidence indicates that VEGFR inhibition alone is usually not sufficient to block the tumor progress. The potential of some agents targeting VEGFR owes partially to the simultaneous inhibition of additional targets in other signaling pathways. In this review, the crosstalk between VEGFR2 and the additional targets in other signaling pathways, such as EGFR, MET, FGFR, PDGFR, c-Kit, Raf, PI3K and HDAC, and the synergistic effects derived from multitarget activities against these crosstalks are discussed. We also briefly describe the multitarget inhibitors in clinical trials or reported in the literature and patents under the different multitarget categories involving VEGFR2.

A real-time fluorescence turn-on assay for trypsin based on a conjugated polyelectrolyte

We report a continuous and sensitive fluorescence turn-on assay for trypsin by using an anionic conjugated polyelectrolyte (PPE-CO2H) and a cationic peptide substrate labelled with p-nitroaniline (RxG-pNA). Applications of the assay in trypsin activity study and high-throughput screening of protease inhibitors were demonstrated.

Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System.

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.

An effective method for de novo peptide sequencing based on phosphorylation strategy and mass spectrometry.

An effective method for peptide sequencing based on phosphorylation strategy and UPLC-MS/MS is proposed in this report. A phosphorylation reaction was carried out by mixing model peptide solution with phosphorylation solution. UPLC-MS/MS was used to analyze and characterize the phosphorylated peptides in the optimized ramp collision energy mode. The results illustrated that this phosphorylation approach significantly strengthened the signal intensity of both a(1) and b series ions of the spectra of the modified peptides. It also can be used to effectively distinguish glutamine (Q) and lysine (K) residues in peptides. The feasibility of this approach was validated by analyzing the trypsin-digested BSA. Data suggested that this proposed method could be a useful tool for the de novo peptide sequencing in proteome research.