Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate.

A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, (S)-17b, demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, (S)-17b exhibited excellent in vivo antitumor activity. In addition, compound (S)-17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC50 value of 34.6 µΜ. This novel compound (S)-17b may serve as a new drug candidate for further investigation.

Adjusted degradation of BRD4 S and BRD4 L based on fine structural modifications of the pyrrolopyridone scaffold.

Novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor with the BRD4 protein. The potent degraders on MV-4-11 cells were discovered through structure-activity relationship study. Modification of warhead on pyrrolopyridone BET degraders significantly regulates BRD4 isoform (long and short) protein degradation, which induces differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that the fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN.

A Conformable, Gas-Permeable, and Transparent Skin-Like Micromesh Architecture for Glucose Monitoring.

Monitoring the concentration of useful biomarkers via electronic skins (e-skins) is highly important for the development of wearable health management systems. While some biosensor e-skins with high flexibility, sensitivity, and stability have been developed, little attention has been paid to their long-term comfortability and optical transparency. Here, a conformable, gas permeable, and transparent skin-like Cu2 O@Ni micromesh structural glucose monitoring patch is reported. With its self-supporting micromesh structure, the skin-like glucose monitoring patch exhibits excellent shape conformability, high gas permeability, and high optical transmittance. The skin-like glucose biosensor achieves real-time monitoring of glucose concentrations with high sensitivity (15 420 µA cm-2 mM-1 ), low detection limit (50 nM), fast response time (＜2 s), high selectivity, and long-term stability. These desirable performance properties arise from the synergistic effects of the self-supporting micromesh configuration, high conductivity of the metallic Ni micromesh, and high electrocatalytic activities of the Cu2 O toward glucose. This work presents a versatile and efficient strategy for constructing conformable, gas permeable, and transparent biosensor e-skins with excellent practicability towards wearable electronics.

Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma.

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor 2 was selected as the lead for further structural optimization, which led to the identification of compounds 25 and 35 as the high potency HH inhibitors. Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI, and were equally potent against the clinical resistant mutants and the wild type of smoothened (SMO) receptor with IC50 values around 1 nmol/L. In the resistant MB allograft mice, compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg (TGI = 83.3%) and 10 mg/kg (TGI = 87.6%) doses. Although further modification is needed to improve the pharmacokinetic (PK) parameters, compound 25 represents an efficacious lead compound of GLI inhibitors, possessing optimal safety and tolerance to fight against HH-driven MB.

Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.

According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.

Optimized HSP90 mediated fluorescent probes for cancer-specific bioimaging.

Cancer-specific bioimaging has been correlated with fluorescence-guided tumor therapy, garnering extensive interest from researchers. Herein, a highly efficient tumor-targeting fluorescent probe (NP-001), which is integrated with 4-hydroxy-1,8-naphthalimide and NVP-AUY922, for tumor imaging has been established. 4-Hydroxy-1,8-naphthalimide is a fluorescent molecule with remarkable imaging compatibility. NVP-AUY922 is a heat shock protein 90 (HSP90) inhibitor with preferential tumor selectivity that is conjugated to 4-hydroxy-1,8-naphthalimide as a tumor-targeting ligand. NP-002, a resorcinol-blocked probe which prevented binding with an amino acid residue of the HSP90 ATP binding pocket, was also synthesized as a control. In vitro and ex vivo assays showed that NP-001 could arrest cell proliferation, induce apoptosis and accumulate to inhibit HSP90. Confocal laser scanning microscopy (CLSM) also confirmed that NP-001 could be selectively internalized by tumor cells for cancer-specific bioimaging. Moreover, pharmacokinetic studies and histological analysis also indicated that NP-001 had a relatively longer retention time and showed no major organ-related toxicities. Overall, these encouraging data suggest that NP-001 is a promising new candidate for the early diagnosis of metastatic disease as well as targeted tumor imaging.