Department of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Published: May 2021
AI Article Synopsis
Article Abstract
Structural analysis of the known NIK inhibitor bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by (cell IC: 571 nM). Systematic optimization of this series of analogs led to the discovery of , a potent (cell IC: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat K: 0.32) for in vivo proof of pharmacology studies. The ability of to inhibit tau phosphorylation at the disease-relevant Ser 422 epitope was demonstrated in both a mouse hypothermia and a rat developmental model and provided evidence that modulation of this target may be relevant in the treatment of Alzheimer's disease and other tauopathies.
Viral infections trigger the integrated stress response (ISR) in eukaryotic cells that leads to the activation of eIF2α kinases, the elevation of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and thereby the shutdown of global protein synthesis that viruses rely on to replicate. Coronaviruses and other viruses have evolved various subversion mechanisms to counteract the antiviral ISR. These intricate host-virus interactions may be exploited by pharmacologically activating the host ISR for the development of host-directed antivirals (HDAs), an increasingly relevant area of research.
Transactivation response (TAR) RNA-binding protein 2 (TRBP) plays a critical role in microRNA (miRNA) biosynthesis, with aberrant expression linked to various cancers. Previously, we identified , a phenyloxazole derivative that disrupts the TRBP-Dicer interaction in hepatocellular carcinoma (HCC). In this study, we optimized this scaffold and substituent, leading to the discovery of , a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar inhibitory activity (EC = 0.
Through catalyzing the transfer of methyl groups onto the guanidinium of arginine, protein arginine methyltransferase 5 (PRMT5) was essential to the cell growth of cancer cells. By utilizing a scaffold hopping strategy, a novel series of 3,4-dihydroisoquinolin-1()-one derivatives were designed and synthesized. Through a systematic SAR study, demonstrated excellent PRMT5 inhibitory activity, potent antiproliferative activity against Z-138, favorable pharmacokinetic profiles, and low hERG toxicity.
Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. However, orally active small-molecule osteogenic drugs are not clinically available. Natural coumarin derivatives, such as osthole, exert osteoblastogenic effects.
Commonwealth Scientific and Industrial Research Organisation (CSIRO), Agriculture and Food, Acton, ACT, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Advanced Engineering Biology Future Science Platform, Acton, ACT, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Microbiomes for One Systems Health Future Science Platform, Acton, ACT, Australia.
The use of multi-omic approaches has significantly advanced the exploration of microbial traits, leading to the discovery of new bioactive compounds and their mechanisms of action. Streptomyces sp. MH71 is known for its antifungal properties with potential for use in crop protection.
