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Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.
J Med Chem
January 2025
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.
View Article and Find Full Text PDFDiscovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.
J Med Chem
January 2025
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands.
View Article and Find Full Text PDFTsg101 mimicry of canonical E2 enzymes underlies its role in ubiquitin signaling.
Proc Natl Acad Sci U S A
January 2025
Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794-5222.
Tsg101 is a highly conserved protein best known as an early-functioning component of cellular ESCRT machinery participating in recognition, sorting, and trafficking of cellular cargo to various intracellular destinations. It shares sequence and structural homology to canonical ubiquitin-conjugating (E2) enzymes and is linked to diverse events regulated by Ub signaling. How it might fulfill these roles is unclear.
View Article and Find Full Text PDFKlebsiella pneumoniae Glycoconjugate Vaccine Leads Based on Semi-Synthetic O1 and O2ac Antigens.
Angew Chem Int Ed Engl
December 2024
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.
Klebsiella pneumoniae (KP) is a common opportunistic pathogen that emerged as a new critical threat to human health, due to its hypervirulence and widespread resistance against many antibiotics, including carbapenems. Alternative intervention strategies such as vaccines are not available. Cell-surface lipopolysaccharides (LPS) and capsular polysaccharides (CPS) are attractive targets for vaccine development.
View Article and Find Full Text PDFReducing Numerical Precision Requirements in Quantum Chemistry Calculations.
J Chem Theory Comput
December 2024
RIKEN Center for Computational Science, Kobe 650-0047, Japan.
The abundant demand for deep learning compute resources has created a renaissance in low-precision hardware. Going forward, it will be essential for simulation software to run on this new generation of machines without sacrificing scientific fidelity. In this paper, we examine the precision requirements of a representative kernel from quantum chemistry calculations: the calculation of the single-particle density matrix from a given mean-field Hamiltonian (i.
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