#Human ACE2‑specific benzothiazole-based allosteric #inhibitor against pan ‑ #sarbecoviruses

Computational #design of an ultrapotent #deltacoronavirus miniprotein #inhibitor

Part 27, drug discovery on an “Undruggable” Target.   K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth… | Stan Van Boeckel

Part 27, drug discovery on an “Undruggable” Target.   K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth factors. Direct attempts to inhibit this oncogene with competitive drugs at its GTP‑binding site failed because of its picomolar affinity for GTP and the high intracellular GTP concentration. Mutations in the K‑Ras pathway, such as K‑RasG12C, render the protein constitutively active, driving uncontrolled proliferation and e.g. contributing to ~40% of K‑Ras–driven lung cancers. Until 2013, K‑Ras was considered non‑druggable, but this view shifted when the Shokat lab revealed a hidden allosteric regulatory pocket in K‑RasG12C that becomes accessible when small electrophilic molecules covalently bind the mutant cysteine. This covalent engagement displaces key “protein switches,” biases the protein toward GDP over GTP conformation and prevents Raf binding, thereby shutting down MAPK signaling. Following this breakthrough, Amgen optimized the Shokat group’s early acrylamide fragments into an in‑vivo‑suitable tool compound, ARS‑1620. Extensive crystallography and docking guided the medicinal chemistry cycles that ultimately produced the highly decorated drug sotorasib (approved in 2021). In phase 3 trials in K‑RasG12C‑mutant lung cancer, sotorasib improved progression‑free survival compared with docetaxel, although overall survival was unchanged. That outcome is somewhat disappointing, but there is hope that real‑world drug combination strategies may yet deliver meaningful gains in overall survival.

Part 27, drug discovery on an “Undruggable” Target.   K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth… | Stan Van Boeckel

Part 27, drug discovery on an “Undruggable” Target.   K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth factors. Direct attempts to inhibit this oncogene with competitive drugs at its GTP‑binding site failed because of its picomolar affinity for GTP and the high intracellular GTP concentration. Mutations in the K‑Ras pathway, such as K‑RasG12C, render the protein constitutively active, driving uncontrolled proliferation and e.g. contributing to ~40% of K‑Ras–driven lung cancers. Until 2013, K‑Ras was considered non‑druggable, but this view shifted when the Shokat lab revealed a hidden allosteric regulatory pocket in K‑RasG12C that becomes accessible when small electrophilic molecules covalently bind the mutant cysteine. This covalent engagement displaces key “protein switches,” biases the protein toward GDP over GTP conformation and prevents Raf binding, thereby shutting down MAPK signaling. Following this breakthrough, Amgen optimized the Shokat group’s early acrylamide fragments into an in‑vivo‑suitable tool compound, ARS‑1620. Extensive crystallography and docking guided the medicinal chemistry cycles that ultimately produced the highly decorated drug sotorasib (approved in 2021). In phase 3 trials in K‑RasG12C‑mutant lung cancer, sotorasib improved progression‑free survival compared with docetaxel, although overall survival was unchanged. That outcome is somewhat disappointing, but there is hope that real‑world drug combination strategies may yet deliver meaningful gains in overall survival.

The virus entry #inhibitor ARN-75039 provides therapeutic #protection against #Lassa virus infection in guinea pigs

A #clinical #SARS-CoV-2 #Mpro #inhibitor blocks replication of multiple #enteroviruses and confers oral in vivo protection in animal models

SciTech Chronicles. . . . . . . . .May 8th, 2025

You've got two good eyes and you still can't see. Vol II No 32 455 links Curated Mission Control RSS Feed Wordpress SubStack Comments Buy...

Coadministration of #ribavirin and #arenaviral entry #inhibitor LHF-535 enhances antiviral benefit against authentic #Lassa virus

A #coronavirus assembly #inhibitor that targets the viral #membrane protein

Unveiling the ethylene-inhibiting mechanism of the allelochemical Myrigalone A – Mauro Maver

This study by Heslop-Harrison et al. investigates the allelochemical Myrigalone A and its potential as an ACC oxidase inhibitor, which disrupts ethylene biosynthesis and affects seed germination and plant development. The findings highlight MyA’s promise for agricultural applications, including weed control and stress resilience, with broader implications for sustainable farming practices.