Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor.

Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy.

Discovery of (R)-4-(8-methoxy-2-methyl-1-(1-phenylethy)-1H-imidazo[4,5-c]quinnolin-7-yl)-3,5-dimethylisoxazole as a potent and selective BET inhibitor for treatment of acute myeloid leukemia (AML) guided by FEP calculation.

The functions of the bromodomain and extra terminal (BET) family of proteins have been proved to be involved in various diseases, particularly the acute myeloid leukemia (AML). In this work, guided by free energy perturbation (FEP) calculation, a methyl group was selected to be attached to the 1H-imidazo[4,5-c]quinoline skeleton, and a series of congeneric compounds were synthesized. Among them, compound 10 demonstrated outstanding activity against BRD4 BD1 with an IC value of 1.

Low Toxicity of Metal-Organic Framework MOF-74(Co) Nano-Particles In Vitro and In Vivo.

With the rapid development of metal-organic frameworks (MOF), the toxicity and environmental safety of MOF materials should be thoroughly investigated. The behaviors and bio-effects of MOF materials after oral exposure are largely unknown. In this study, we performed a pilot toxicity evaluation of MOF-74(Co) nanoparticles (NPs) both in vitro and in vivo.

Discovery of 2-Methyl-2-(4-(2-methyl-8-(1-pyrrolo[2,3-]pyridin-6-yl)-1-naphtho[1,2-]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy and .

PI3K/Akt/mTOR signaling pathway is a validated drug target for cancer treatment that plays a critical role in controlling tumor growth, proliferation, and apoptosis. However, no FDA-approved PI3K/mTOR dual inhibitor exists. Thus, a candidate with a better curative effect and lower toxicity is still urgently needed.

Synthesis and biological evaluation of a tumor-selective degrader of PARP1.

Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition.

Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer.

Triple negative breast cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC.

Biocompatible zinc gallogermanate persistent luminescent nanoparticles for fast tumor drainage lymph node imaging in vivo.

Tumor drainage lymph node identification and dissection are crucial for the oncological surgery to prevent/delay the recurrence. However, commercial imaging reagents distinguish the lymph nodes by staining them dark, which would be seriously interfered by blood and surrounding tissues. In this study, we reported the Cr/Pr-doped zinc gallogermanate persistent luminescent nanoparticles (PLNPs) for fast tumor drainage lymph node imaging with high contrast.

Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold.

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6.

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design.

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, , which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2'-Oxybis(ethylamine) linker. The and assays showed is a potent selective ALKi with low toxicity to normal cells.

Discovery of a PROTAC targeting ALK with in vivo activity.

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy.

Toxicity and photosynthetic inhibition of metal-organic framework MOF-199 to pea seedlings.

Metal-organic framework (MOF) materials are star materials with unique structures and properties. To ensure safe production and applications, the toxicity and environmental hazards of MOF materials should be thoroughly investigated. However, the environmental impact of MOF materials on plants is completely unknown.

Discovery of 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline as a novel c-myc inhibitor against colorectal cancer in vitro and in vivo.

Proto-oncogene c-Myc plays an essential role in the development of colorectal cancer (CRC), since downregulation of c-Myc inhibits intestinal polyposis, which is the most cardinal pathological change in the development of CRC. Herein, a series of novel phenoxy-N-phenylaniline derivatives were designed and synthesized. The cytotoxicity activities of all the derivatives were measured by MTT assay in different colon cancer cells, 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline (42) was discovered, the lead compound 42 with excellent cytotoxicity activity of IC = 0.

Fast Identification and Quantification of Graphene Oxide in Aqueous Environment by Raman Spectroscopy.

Today, graphene nanomaterials are produced on a large-scale and applied in various areas. The toxicity and hazards of graphene materials have aroused great concerns, in which the detection and quantification of graphene are essential for environmental risk evaluations. In this study, we developed a fast identification and quantification method for graphene oxide (GO) in aqueous environments using Raman spectroscopy.

Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC of 0.

Synthesis and biological evaluation of 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1)-ones as cisplatin sensitizers.

A series of novel 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1)-one derivatives were synthesized and their anti-cancer as well as cisplatin sensitization activities were evaluated. Among them, compounds and exhibited significant cisplatin sensitization activity against HCT116. Hoechst staining and annexin V-FITC/PI dual-labeling studies demonstrated that the combination of / and cisplatin can induce tumour cell apoptosis.

Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors.

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.