Genentech, Inc. , One DNA Way , South San Francisco , California 94080 , United States.
Published: July 2019
AI Article Synopsis
Article Abstract
A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.
Background: We have previously developed a candidate therapeutic HPV DNA vaccine (pBI-11) encoding mycobacteria heat shock protein 70 linked to HPV16/18 E6/E7 proteins for the control of advanced HPV-associated oropharyngeal cancer (NCT05799144). While naked DNA vaccines are readily produced, stable, and well tolerated, their potency is limited by the delivery efficiency. Here we compared three different IM delivery strategies, including intramuscular (IM) injection, either with a needle alone or with electroporation at the injection site, and a needle-free injection system (NFIS), for their ability to elicit gene expression and to improve the potency of pBI-11 DNA vaccine.
This study utilized deep learning to optimize antihypertensive peptides from whey protein hydrolysate. Using the Large Language Models (LLMs), we identified an optimal multienzyme combination (MC5) with an ACE inhibition rate of 89.08% at a concentration of 1 mg/mL, significantly higher than single-enzyme hydrolysis.
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
New derivatives 6a-m with benzimidazole-indole-amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose.
Physical Chemistry 1, University of Lund, S-221 00 Lund, Sweden; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark. Electronic address:
New antimicrobial and anti-inflammatory therapeutics are needed because of antibiotic resistance development and resulting complications such as inflammation, ultimately leading to septic shock. The antimicrobial effects of various nanoparticles (NPs) are currently attracting intensive research interest. Although various NPs display potent antimicrobial effects against strains resistant to conventional antibiotics, the therapeutic use of such materials is restricted by poor selectivity between bacteria and human cells, leading to adverse side effects.
College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510530, China. Electronic address:
Right open reading frame kinase 2 (RIOK2) is an atypical serine threonine kinase which plays an important role in regulating ribosome synthesis and cell cycle progression. RIOK2 has been implicated in multiple human cancers and is a potential target for cancer treatment. We previously reported the discovery of CQ211 as a potent and selective RIOK2 inhibitor.
