Discovery of novel pyrrolo[2,3-d]pyrimidines as potent menin-mixed lineage leukemia interaction inhibitors.

To interfere the Menin-MLL interaction using small molecular inhibitors has been shown as new treatment of several special hematological malignancies. Herein, a series of Menin-MLL interaction inhibitors with pyrrolo[2,3-d]pyrimidine scaffold were designed, synthesized and evaluated. Among them, compound A6 exhibited potent binding affinity with an IC50 value of 0.38 µM, and strong anti-proliferative activity against MV4-11 cells with an IC50 value of 1.07 µM. Further study showed A6 reduced the transcriptional levels of HOXA9 and MEIS1 genes. Moreover, A6 induced cellular apoptosis, arrested the cell cycle in G0/G1 phase, and reversed the differentiation arrest in a concentration-dependent manner. This study suggested compound A6 was as a novel potent Menin-MLL interaction inhibitor, and it proved that introduction of 4-amino pyrrolo[2,3-d]pyrimidine to occupy the P10 hydrophobic pocket was new idea for design of novel Menin-MLL interaction inhibitors.

Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors.

The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 µM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors.

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1, A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2-d]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.

Discovery of potent and selective PI3Kδ inhibitors bearing amino acid fragments.

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and ß. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.

Metabolic reprogramming enables the auxiliary diagnosis of breast cancer by automated breast volume scanner.

Breast cancer is the leading cause of female cancer-related deaths worldwide. New technologies with enhanced sensitivity and specificity for early diagnosis and monitoring of postoperative recurrence are in critical demand. Automatic breast full volume scanning system (ABVS) is an emerging technology used as an alternative imaging method for breast cancer screening. Despite its improved detection rate of malignant tumors, ABVS cannot accurately stage breast cancer preoperatively in 30-40% of cases. As a major hallmark of breast cancer, the characteristic metabolic reprogramming may provide potential biomarkers as an auxiliary method for ABVS. Objective: The objective of this study was to identify differential metabolomic signatures between benign and malignant breast tumors and among different subtypes of breast cancer patients based on untargeted metabolomics and improve breast cancer detection rate by combining key metabolites and ABVS. Methods: Untargeted metabolomics approach was used to profile serum samples from 70 patients with different subtypes of breast cancer and benign breast tumor to determine specific metabolomic profiles through univariate and multivariate statistical data analysis. Results: Metabolic profiles correctly distinguished benign and malignant breast tumors patients, and a total of 791 metabolites were identified. There were 54 different metabolites between benign and malignant breast tumors and 17 different metabolites between invasive and non-invasive breast cancer. Notably, the missed diagnosis rate of ABVS could be reduced by differential metabolite analysis. Moreover, the diagnostic performance analyses of combined metabolites (pelargonic acid, N-acetylasparagine, and cysteine-S-sulfate) with ABVS performance gave a ROC area under the curve of 0.967 (95% CI: 0.926, 0.993). Conclusions: Our study identified metabolic features both in benign and malignant breast tumors and in invasive and non-invasive breast cancer. Combined ultrasound ABVS and a panel of differential serum metabolites could further improve the accuracy of preoperative diagnosis of breast cancer and guide surgical therapy.

Integrated green complexing agent and biochar modified nano zero-valent iron for hexavalent chromium removal: A characterisation and performance study.

In this study, nano zero-valent iron (nZVI) was loaded on biochar (BC) prepared from recycled waste peanut shells. The loaded BC in the nZVI@BC composite was assumed to weaken the agglomeration of nZVI and the environmentally-friendly complexing agents sodium citrate (Cit) and sodium carboxymethyl cellulose (CMC) were used to establish Cit-nZVI@BC and CMC-nZVI@BC for the effective removal of Cr(VI) from aqueous environments. The characterisation results suggested that Cit and CMC not only inhibited the oxidation of nZVI, but also effectively improved its reactivity. The experimental results demonstrated that the Cr(VI) removal efficiency by nZVI was less than 20%, while CMC-nZVI@BC enhanced the Cr(VI) removal efficiency to 80.73%, because CMC was coated on the nZVI surface for anti-passivation and improved the surface activity of nanoparticles. In addition, the Cr(VI) removal efficiency reached almost 100% with Cit-nZVI@BC, and the citrate dissociated the passivation layer on the surface of the zero-valent iron particles to ensure the reactivity of the zero-valent iron. The reaction mechanism of Cit-nZVI@BC includes adsorption, reduction, and co-precipitation, whereas CMC-nZVI@BC also involves surface complexation reactions. The kinetic studies revealed that the removal of Cr(VI) by Cit-nZVI@BC and CMC-nZVI@BC followed the second-order reaction kinetic model, and the reaction rates of Cit-nZVI@BC and CMC-nZVI@BC were both higher than that of nZVI. The results indicate that the prepared systems are promising for Cr(VI) remediation in contaminated environments.

Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021).

INTRODUCTION: Chromosomal translocations involving the mixed-lineage leukemia (MLL, KMT2A, MLL1) genes result in the production of MLL fusion proteins, which cause abnormal transcriptional regulation leading to acute leukemia (AL). Menin (MEN1) protein is essential for MLL to regulate the expression of related target genes. High-affinity interactions between the amino terminus of MLL proteins and Menin proteins are required to mediate the oncogenic transformation of MLL fusion proteins. Therefore, inhibition of Menin and MLL interaction is a potential therapeutic strategy for MLL rearrangement (MLL-r) leukemia and can provide a new choice for treatment of other diseases. Therefore, researchers have made great efforts to explore small-molecule Menin-MLL interaction inhibitors. AREAS COVERED: This review is to provide an overview of the patented Menin-MLL protein-protein interaction inhibitors from 2014 to 2021. EXPERT OPINION: Menin-MLL interaction inhibitors have therapeutic potential in the treatment of acute leukemia, such as AML and ALL. SNDX-5613 and KO-539 have been granted orphan drug designation by the FDA for treatment of refractory/relapsed leukemia and AML, respectively. In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.

Sodium citrate and biochar synergistic improvement of nanoscale zero-valent iron composite for the removal of chromium (â ¥) in aqueous solutions.

Sodium citrate (SC) is a widely-used food and industrial additive with the properties of complexation and microbial degradation. In the present study, nano-zero-valent iron reaction system (SC-nZVI@BC) was successfully established by modifying nanoscale zero-valent iron (nZVI) with SC and biochar (BC), and was employed to remove Cr(Ⅵ) from aqueous solutions. The nZVI, SC-nZVI and SC-nZVI@BC were characterized and compared using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analyses (TGA), vibrating sample magnetometer (VSM), scanning electron microscope (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The results showed that nZVI was successfully loaded on the biochar, and both the agglomeration and surface passivation problems of nanoparticles were well resolved. The dosage of SC, C:Fe, initial pH and Cr(Ⅵ) concentration demonstrated direct effects on the removal efficiency. The maximum Cr(Ⅵ) removal rate and the removal capacity within 60 min were 99.7% and 199.46 mg/g, respectively (C:Fe was 1:1, SC dosage was 1.12 mol.%, temperature was 25°C, pH = 7, and the original concentration of Cr(Ⅵ) was 20 mg/L). The reaction confirmed to follow the pseudo-second-order reaction kinetics, and the order of the reaction rate constant k was as follows: SC-nZVI@BC > nZVI@BC > SC-nZVI > nZVI. In addition, the mechanism of Cr(Ⅵ) removal by SC-nZVI@BC mainly involved adsorption, reduction and co-precipitation, and the reduction of Cr(Ⅵ) to Cr(Ⅲ) by nano Fe0 played a vital role. Findings from the present study demonstrated that the SC-nZVI@BC exhibited excellent removal efficiency toward Cr(Ⅵ) with an improved synergistic characteristic by SC and BC.

The Mediating Role of Family and Cultural Food Beliefs on the Relationship between Family Communication Patterns and Diet and Health Issues across Racial/Ethnic Groups.

Consumption of red meat has been linked to a variety of health issues, yet Americans are resistant to reducing their meat consumption. Family communication environments shape beliefs about food and meat consumption, and therefore are locations for potential interventions to change the way people think about food. Families are embedded in cultures, and both family and cultural norms shape beliefs about what people should eat. This study (N = 773) is interested in understanding how family communication is associated with food beliefs, meat consumption, and health issues across three racial/ethnic groups: Black/African American (n = 256), Hispanic (n = 260), non-Hispanic White (n = 257). Structural equation modeling results showed that conversation orientation was consistently associated with stronger endorsement of family cultural food beliefs across race/ethnicity groups. Family food beliefs were associated with either more health issues or more meat consumption depending on race/ethnicity and mediated the association between conversation orientation and health issues/meat consumption. Conversation orientation moderated the association between conformity orientation and food beliefs for Hispanic and non-Hispanic White participants. Implications for family communication patterns theory and health scholars are discussed along with recommendations for culturally tailored family-focused health interventions.

FamilyLog: A Mobile System for Monitoring Family Mealtime Activities.

Research has shown that family mealtime plays a critical role in establishing good relationships among family members and maintaining their physical and mental health. In particular, regularly eating dinner as a family significantly reduces prevalence of obesity. However, American families with children spend only 1 hour on family meals while three hours watching TV on an average work day. Fine-grained activity-logging is proven effective for increasing self-awareness and motivating people to modify their life styles for improved wellness. This paper presents FamilyLog - a practical system to log family mealtime activities using smartphones and smartwatches. FamilyLog automatically detects and logs details of activities during the mealtime, including occurrence and duration of meal, conversations, participants, TV viewing etc., in an unobtrusive manner. Based on the sensor data collected from real families, we carefully design robust yet lightweight signal features from a set of complex activities during the meal, including clattering sound, arm gestures of eating, human voice, TV sound, etc. Moreover, FamilyLog opportunistically fuses data from built-in sensors of multiple mobile devices available in a family through an HMM-based classifier. To evaluate the real-world performance of FamilyLog, we perform extensive experiments that consist of 77 days of sensor data from 37 subjects in 8 families with children. Our results show that FamilyLog can detect those events with high accuracy across different families and home environments.