Ming Ji

Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors

Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors.

Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype

Glioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage.

Poly (ADP-ribose) polymerases inhibitor, Zj6413, as a potential therapeutic agent against breast cancer

Poly (ADP-ribose) polymerases (PARPs) facilitate repairing of cancer cell DNA damage as a mean to promote cancer proliferation and metastasis. Inhibitors of PARPs which interfering DNA repair, in context of defects in other DNA repair mechanisms, can thus be potentially exploited to inhibit or even kill cancer cells. However, nondiscriminatory inhibition of PARPs, such as PARP2, may lead to undesired consequences. Here, we demonstrated the design and development of the Zj6413 as a potent and selective PARP1 catalytic inhibitor. It trapped PARP1/2 at damaged sites of DNA. As expected, the Zj6413 showed notable anti-tumor activity against breast cancer gene (BRCA) deficient triple negative breast cancers (TNBCs). Zj6413 treated breast cancers (BCs) showed an elevated level of DNA damage evidenced by the accumulation of γ-H2AX foci and DNA damaged related proteins. Zj6413 also induced G2/M arrest and cell death in the MX-1, MDA-MB-453 BC cells, exerted chemo-sensitizing effect on BRCA proficient cancer cells and potentiated Temozolomide (TMZ)s cytotoxicity in MX-1 xenograft tumors mice. In conclusion, our study provided evidence that a new PARP inhibitor strongly inhibited the catalytic activity of PARPs, trapped them on nicked DNA and damaged the cancer cells, eventually inhibiting the growth of breast tumor cells in vitro and in vivo.

Discovery of novel quinazoline-2,4(1 H ,3 H )-dione derivatives as potent PARP-2 selective inhibitors

The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.

The Development of a Biotinylated NAD+-Applied Human Poly(ADP-Ribose) Polymerase 3 (PARP3) Enzymatic Assay:

Poly(ADP-ribose) polymerase 3 (PARP3) is an important member of the PARP family and shares high structural similarities with both PARP1 and PARP2. The biological roles of PARP3 are currently under investigation; however, several key reports indicate the integral roles of PARP3 in DNA damage repair, and thus it has been investigated as a novel target in oncology. It is clear that the identification of selective PARP3 inhibitors would further advance the understanding of the biological roles of PARP3. Herein, we describe a modified PARP3 screening assay using biotinylated NAD+ as the specialized substrate. This method relies on the activity of PARP3 to transfer the biotinylated NAD+ onto a histone protein to form ADP-ribosylated histone. The biotin label on this histone protein is then detected and quantifies the intrinsic enzymatic activity of PARP3. We optimized the assay with respect to the histone, NAD+/biotinylated NAD+ mixture, DNA, and PARP3. Our developed screening system was then validated with a reported selective PARP3 inhibitor, ME0328, as well as utilizing five other clinically available PARP1/2 inhibitors. We demonstrated that our assay system was sensitive, efficient, and economical, and we reason that it could be useful for the development of highly selective PARP3 inhibitors in the future.

Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

Bt354 as a New STAT3 Signaling Pathway Inhibitor against Triple Negative Breast Cancer

Abstract Inhibition of the signal transducer and activator of transcription 3 (STAT3) signalling pathway has been considered as a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we screened 1563 compounds and identified Bt354 as a new small-molecule inhibitor of the STAT3 signalling pathway. The effect of Bt354 on STAT3 activity was initially screened and Bt354 significantly inhibited STAT3 activity in a dual luciferase assay. Bt354 inhibited the proliferation of cancer cells in a dose- and time-dependent manner. The phosphorylation of STAT3 at Y705 was suppressed without affecting the phosphorylation of STAT3 at S727 in breast cancer cells. Furthermore, Bt354 inhibited the nuclear translocation of STAT3 and consequently induced cell growth inhibition, apoptosis and cell cycle G2/M arrest in triple negative breast cancer cells. In vivo, Bt354 also inhibited tumour growth in MDA-MB-435 and MDA-MB-231 xenograft mice without affecting body weight. Computational modelling showed that Bt354 could bind to the SH2 domain of STAT3. These findings suggest that Bt354 may be a potent anticancer agent for STAT3-activated triple negative breast cancer cells.

Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A

A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity.

Validating a selective S1P1 receptor modulator Syl930 for psoriasis treatment

Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment. Here, we test a newly developed selective S1P1 modulator, Syl930, in four different psoriasis animal models. Our data reveals that oral administration of Syl930 can induce strong anti-proliferative and anti-inflammatory effects. Specifically, Syl930 decreases the pathological thickening of back skin induced by sodium lauryl sulfate (SLS), inhibits the proliferation of basal cells in a vaginal epithelium model and increases the granular layer scales in a mouse tail assay. Moreover, Syl930 can ameliorate the parakeratosis and acanthosis as well as improve granular layer composition and decrease the thickening of epidermis in a propranolol-induced guinea pig psoriasis model. Therefore, we demonstrate that Syl930 is a promising candidate for psoriasis therapy in clinical.

Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.