Structure-based design of ester compounds to inhibit MLL complex catalytic activity by targeting mixed lineage leukemia 1 (MLL1)-WDR5 interaction.

WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein-protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1-WDR5 PPI. These inhibitors efficiently inhibited the histone methyltransferase activity in vitro. Especially, WL-15 was one of the most potent inhibitors, blocking the interaction of MLL1-WDR5 with IC50 value of 26.4nM in competitive binding assay and inhibiting the catalytic activity of MLL1 complex with IC50 value of 5.4µM. Docking model indicated that ester compounds suitably occupied the central cavity of WDR5 protein and recapitulated the interactions of WDR5-0103 and the hydrophobic groups and key amino greatly increased the activity in blocking MLL1-WDR5 PPI.

High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity.

MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 µM) in HMT assay.

Discovery and optimization of new benzofuran derivatives against p53-independent malignant cancer cells through inhibition of HIF-1 pathway.

p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.

Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5.

MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 µM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

[Analysis on differences between soft-tissue and hard-tissue profile in malocclusions].

OBJECTIVE: To study the characteristics of soft-tissue integument and the differences between soft-tissue and hard-tissue topography in malocclusions. METHODS: 144 female patients, 12-15 years old, were selected. They were divided into class I, class II and class III groups according to the value of angle ANB which was measured on the pre-treatment cephalographs. Each group had 48 patients. Each patient had same type of skeletal pattern and occlusal pattern, full set of permanent teeth and none of cranofacial soft-tissue and hard-tissue diseases. 4 pairs of measurements describing soft-tissue and hard-tissue sagittal facial pattern and the prominence of lips and incisors were measured on each cephalograph. They were angle SnNsB', angle ANB, angle NsSnPos, angleNAPo, UL-SnPos, UI-APo, LL-SnPos and LI-APo. The distribution of soft-tissue sagittal facial pattern in each skeletal group was analyzed. The differences between angle SnNsB' and angle ANB, angle NsSnPos and angle NAPo, UL-SnPos and UI-APo, LL-SnPos and LI-APo were calculated in each patient. Then we calculated the means and the ranges of these differences in each group, the probability of positive and negative difference between each pair of measurements in each group were calculated too. Chi2 test on those probabilities were performed between the three groups. The mean difference between each pair of measurements was then analyzed by ANOVA between the three groups. RESULTS: The disharmony between soft-tissue and hard-tissue sagittal facial pattern was found in 20%-30% of malocclusion patients. There were more or less differences between soft-tissue and hard-tissue topography and the ranges of their variation were quite wide. The soft-tissue integument increasingly tended to augment the convexity of soft-tissue facial profile when skeletal pattern varied from class II to class I to class III, at the same time, tended to increase upper lip prominence and decrease lower lip prominence. CONCLUSION: On the average, soft-tissue integument tends to camouflage the abnormality of hard-tissue topography. But as to individual, the relative independence of soft-tissue integument makes it important to notice the influence of soft tissue on treatment planning and results.

[The changes of subgingival microbials during periodontal maintenance in patients with gingivitic and wearing fixed orthodontic appliances].

OBJECTIVE: To investigate the microbiological changes of subgingival microbials in patients with gingivitis and wearing fixed orthodontic appliances. METHODS: 48 subjects (10 to 17 years old) with gingivitis, and wearing fixed orthodontic appliances, were divided randomly into three groups (placebo, NS and CH). Placebo group had normal saline mouthrinse; only and no oral hygiene instruction (OHI). The NS group had OHI and normal saline mouthrinse; The CH group had OHI and 0.12% chlorhexidine gluconate mouthrinse. Bacterial examinations were carried out on baseline, one week, one month and three months after scaling. The bacterial examination was carried out. The percentage of coccus, bacillus and spirochete was calculated. RESULTS: In placebo group and NS group, the percentage of coccus increased up to the third examination then dropped down. The spirochete's percentage changed inversely. CH group maintained an increasing trend in coccus' percentage and decreasing trend in spirochete's percentage. The percentage changes of coccus and bacillus between placebo group and CH group are statistically significant (P < 0.05). CONCLUSIONS: During the three-month examination, the CH group had better microbiologic change than the other two groups.