Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC50 > 30 µM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC50 = 2.8 µM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers.

Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a highly attractive therapeutic target for treating Kirsten rat sarcoma viral oncogene (KRAS) mutant cancers. In this work, a series of guanidine-based SHP2 allosteric inhibitors were discovered via virtual screening and rational structural optimization. Notably, lead compound 23 with potent SHP2 inhibitory activity (IC50 = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound 23 featured great in vivo pharmacokinetic properties (AUCpo = 4320 nM·h; F = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 23 is a potential lead compound for the development of SHP2 allosteric inhibitors to treat KRAS mutant cancers. Moreover, these guanidine-based scaffolds may provide an opportunity to mitigate the potential safety risks of the alkyl amine motif predominately incorporated in current SHP2 allosteric inhibitors.

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling.

Son of sevenless homologue 1 (SOS1) protein is universally expressed in cells and plays an important role in the RAS signaling pathway. Specifically, this protein interacts with RAS in response to upstream stimuli to promote guanine nucleotide exchange in RAS and activates the downstream signaling pathways. Thus, targeting SOS1 is a new approach for treating RAS-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of SOS1 and focus on recent advances in the discovery of activators, inhibitors, and PROTACs that target SOS1. This review aims to provide a timely and updated overview on the strategies for targeting SOS1 in cancer therapy.

Characterization of the bacterial microbiota in different gut and oral compartments of splendid japalure (Japalura sensu lato).

BACKGROUND: Gut and oral microbes form complex communities and play key roles in co-evolution with their hosts. However, little is understood about the bacterial community in lizards. RESULTS: In this study, we investigated the gut and oral bacterial communities in Japalura sensu lato from Sichuan Province, China, using 16S rRNA gene sequencing. Results showed that Bacteroidota (36.5%) and Firmicutes (32.8%) were the main phyla in the gut, while Proteobacteria, Bacteroidota, Firmicutes, and Actinobacteriota were the dominant phyla in the oral cavity. 16 S rRNA sequencing analysis of fecal samples showed that: (1) Bacteroidota was the most abundant in Japalura sensu lato, which was different from the bacterial community of insectivorous animals; (2) Bacteroidota, Firmicutes, Actinobacteriota, Fusobacteriota, and Cyanobacteria were the most abundant phylum in Japalura sensu lato. (3) Proteobacteria was the dominant phylum in Japalura sensu lato and other domestic insectivorous lizards (Shinisaurus crocodilurus, Phrynocephalus vlangalii, and Takydromus septentrionalis); (4) Comparing with the bacterial community of Shinisaurus crocodilurus, Phrynocephalus vlangalii, Takydromus septentrionalis, Liolaemus parvus, L. ruibali, and Phymaturus williamsi, Desulfobacterota was uniquely present in the gut of Japalura sensu lato. 16 S rRNA sequencing of oral samples showed that Chloroflexi and Deinococcota phyla were enriched in the oral cavity, which may have a significant influence on living in extreme environments. CONCLUSIONS: Thus, based on 16 S rRNA sequencing analysis of the community composition of the gut and oral microbiomes, this study firstly represents a foundation for understanding the gut and oral microbial ecology of Japalura sensu lato, and constitutes a detail account of the diversity of the microbiota inhabiting the gut and oral cavity of Japalura sensu lato. Further researches will continue to reveal how gut and oral microbial communities may be impacting the ecology and evolution of lizards.

Discovery of a Novel Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer.

The treatment of triple-negative breast cancer (TNBC) remains a huge clinical challenge and dual-targeted small-molecule drugs might provide new therapeutic options for this type of breast cancer. In this work, we discovered a series of SHP2 and CDK4 dual inhibitors through a fused pharmacophore strategy and structural optimization. Notably, lead compound 10 with excellent SHP2 (IC50 = 4.3 nM) and CDK4 (IC50 = 18.2 nM) inhibitory activities effectively induced G0/G1 arrest to prevent the proliferation of TNBC cell lines. Furthermore, compound 10 showed great in vivo pharmacokinetic properties (F = 45.8%) and exerted significant antitumor efficacy in the EMT6 syngeneic mouse model. Western blotting and immunohistochemical analysis confirmed that 10 effectively targeted on both SHP2 and CDK4 and activated the immune response in tumors. These results indicate that lead compound 10, as the first SHP2 and CDK4 dual inhibitor, merits further development for treating TNBC.

Molecular Characterization of a Novel Budgerigar Fledgling Disease Virus Strain From Budgerigars in China.

Budgerigar fledgling disease virus (BFDV) is the causative polyomavirus of budgerigar fledgling disease, an important avian immunosuppressive disease in budgerigars (Melopsittacus undulatus). In the current study, we explored the etiological role and molecular characteristics of BFDV. We identified a novel BFDV strain, designated as SC-YB19, belonging to a unique cluster with three other domestic strains (WF-GM01, SD18, and APV-P) and closely related to Polish isolates based on complete sequences. Sequence analysis showed that SC-YB19 had an 18-nucleotide (nt) deletion in the enhancer region, corresponding to the sequence position 164-181 nt, which differed significantly from all other BFDV strains. Based on sequence alignment, three unique nucleotide substitutions were found in VP4 (position 821), VP1 (position 2,383), and T-antigen (position 3,517) of SC-YB19, compared with SD18, WF-GM01, QDJM01, HBYM02, APV7, and BFDV1. Phylogenetic analyses based on complete sequences suggested that SC-YB19, along with the domestic WF-GM01, SD18, and APV-P strains, formed a single branch and were closely related to Polish, Japanese, and American isolates. These results demonstrate that BFDV genotype variations are co-circulating in China, thus providing important insight into BFDV evolution.

What will happen when thermoresponsive poly(N-isopropylacrylamide) is tethered on poly(ionic liquid)s?

The thermoresponsive ionic liquid diblock copolymer of poly[1-(4-vinylbenzyl)-3-methylimidazolium tetrafluoroborate]-block-poly(N-isopropylacrylamide) (P[VBMI][BF4]-b-PNIPAM) containing a hydrophilic poly(ionic liquid) block of P[VBMI][BF4] is prepared by sequential reversible addition-fragmentation chain transfer (RAFT) polymerization. This P[VBMI][BF4]-b-PNIPAM exhibits an abnormal thermoresponsive phase transition at a temperature above the phase transition temperature (PTT) of the PNIPAM block. For P[VBMI][BF4]-b-PNIPAM including a short P[VBMI][BF4] block, its aqueous solution becomes turbid at a temperature above the PTT of the thermoresponsive PNIPAM block, whereas for P[VBMI][BF4]-b-PNIPAM containing a relatively long P[VBMI][BF4] block even in the case of a relatively long PNIPAM block, the aqueous solution remains transparent at a temperature far above the PTT of the PNIPAM block, although a soluble-to-insoluble phase transition of the PINIPAM block is confirmed by dynamic light scattering (DLS) analysis and variable temperature 1H NMR analysis. The reason that P[VBMI][BF4]-b-PNIPAM exhibits an abnormal thermoresponse is discussed and ascribed to the highly hydrophilic and charged poly(ionic liquid) block of P[VBMI][BF4] leading to the formation of small-sized micelles at a temperature above the PTT.