Discovery of the 2,4-disubstituted quinazoline derivative as a novel neddylation inhibitor for tumor therapy.

Overactivation of neddylation has been found in a number of common human tumor-related diseases. In recent years, targeting the neddylation pathway has become an appealing anti-cancer strategy, and it is critical to find neddylation inhibitors with novel structures and higher efficacy. Here, we present the discovery of novel inhibitors of the NEDD8-activating enzyme (NAE) and their antitumor activity in vitro. All synthesized 1,4-disubstituted piperidine compounds were evaluated for antiproliferative activity against MGC-803, MCF-7, A549, and KYSE-30 cells. Among five representative compounds, III-26 bearing a quinazoline motif was identified as the lead one due to the fact that it significantly hindered the neddylation of Cullin1. Cellular mechanisms elucidated that III-26 inhibited the proliferation, migration, and invasion of UBC12-overexpressed MGC-803 cell lines, as well as induced apoptosis and arrested the cell cycle at G2/M phase. Importantly, III-26 reduced NAE activity, thus selectively preventing neddylation of Cullin3 and Cullin1 over other Cullin members. At a dose of 4 µM, III-26 virtually entirely blocked UBC12-NEDD8 conjugation in MGC-803 cells. Our molecular modeling and kinetic investigation suggested that this compound may function as a non-covalent inhibitor of NAE.

Biochemical and structural characterization of chlorhexidine as an ATP-assisted inhibitor against type 1 methionyl-tRNA synthetase from Gram-positive bacteria.

Methionyl-tRNA synthetase (MetRS) catalyzes the attachment of l-methionine (l-Met) to tRNAMet to generate methionyl-tRNAMet, an essential substrate for protein translation within ribosome. Owing to its indispensable biological function and the structural discrepancies with human counterpart, bacterial MetRS is considered an ideal target for developing antibacterials. Herein, chlorhexidine (CHX) was identified as a potent binder of Staphylococcus aureus MetRS (SaMetRS) through an ATP-aided affinity screening. The co-crystal structure showed that CHX simultaneously occupies the enlarged l-Met pocket (EMP) and the auxiliary pocket (AP) of SaMetRS with its two chlorophenyl groups, while its central hexyl linker swings upwards to interact with some conserved hydrophobic residues. ATP adopts alternative conformations in the active site cavity, and forms ionic bonds and water-mediated hydrogen bonds with CHX. Consistent with this synergistic binding mode, ATP concentration-dependently enhanced the binding affinity of CHX to SaMetRS from 10.2 µM (no ATP) to 0.45 µM (1 mM ATP). While it selectively inhibited two representative type 1 MetRSs from S. aureus and Enterococcus faecalis, CHX did not show significant interactions with three tested type 2 MetRSs, including human cytoplasmic MetRS, in the enzyme inhibition and biophysical binding assays, probably due to the conformational differences between two types of MetRSs at their EMP and AP. Our findings on CHX may inspire the design of MetRS-directed antimicrobials in future.

Design, synthesis and biological evaluation of novel tubulin inhibitors targeting colchicine sites.

Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.

APJ/apelin: A promising target for the treatment of retinopathy of prematurity.

Retinopathy of prematurity is a noticeable retinal abnormality causing common blindness in children. An uncontrolled retinal vasculature in retinopathy of prematurity inflicts vision loss in numerous children despite the accessibility to a wide range of clinical treatments prescribed for retinopathy of prematurity. Apelin/APJ [class A (rhodopsin-like) G-protein-coupled receptor] signaling regulates retinopathy of prematurity augmented with uncontrolled angiogenesis. Antagonists targeting pathological apelin/APJ-signaling-induced angiogenesis could be effective in attenuating retinopathy of prematurity. The therapeutic proficiency of antagonists in diverse modalities: peptides, bioactive molecules and antibodies, targeting apelin peptides or the APJ receptor is discussed in this review. We hypothesize the antagonists could effectively attenuate the retinal vasculature triggered by apelin/APJ signaling activation governing vision impairment in young children.

The role of MOZ/KAT6A in hematological malignancies and advances in MOZ/KAT6A inhibitors.

Hematological malignancies, unlike solid tumors, are a group of malignancies caused by abnormal differentiation of hematopoietic stem cells. Monocytic leukemia zinc finger protein (MOZ), a member of the MYST (MOZ, Ybf2/Sas3, Sas2, Tip60) family, is a histone acetyltransferase. MOZ is involved in various cellular functions: generation and maintenance of hematopoietic stem cells, development of erythroid cells, B-lineage progenitors and myeloid cells, and regulation of cellular senescence. Studies have shown that MOZ is susceptible to translocation in chromosomal rearrangements to form fusion genes, leading to the fusion of MOZ with other cellular regulators to form MOZ fusion proteins. Different MOZ fusion proteins have different roles, such as in the development and progression of hematological malignancies and inhibition of cellular senescence. Thus, MOZ is an attractive target, and targeting MOZ to design small-molecule drugs can help to treat hematological malignancies. This review summarizes recent progress in biology and medicinal chemistry for the histone acetyltransferase MOZ. In the biology section, MOZ and cofactors, structures of MOZ and related HATs, MOZ and fusion proteins, and roles of MOZ in cancer are discussed. In medicinal chemistry, recent developments in MOZ inhibitors are summarized.

NQO1-Selective Activated Prodrug of Triptolide: Synthesis and Antihepatocellular Carcinoma Activity Evaluation.

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Due to its poor response to conventional chemotherapy drugs, the prognosis for its survival is the worst. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an attractive anticancer target due to its overexpression in HCC. Although triptolide (TP) possesses potent antitumor activity, its clinical practice is greatly limited due to its general toxicities and narrow therapeutic window. Herein, we develop an NQO1-selective activated TP analog, named CX-23, which exhibited antiproliferation of HepG2 over normal hepatocytes in vitro. In vivo study shows that CX-23 can not only prevent the hepatocellular carcinoma progression but also migrate the liver and kidney toxicity. These findings indicate that NQO1 may serve as a targeted delivery system to release an antitumor reagent and that CX-23 may be a promising lead for developing targeted antihepatocellular carcinoma drugs.