A5042923934- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Ferroelectric and Negative Capacitance Devices
- CAR-T cell therapy research
- Enhanced Oil Recovery Techniques
- Immunotherapy and Immune Responses
- Microfluidic and Capillary Electrophoresis Applications
- Drilling and Well Engineering
- Immune Response and Inflammation
- Cancer therapeutics and mechanisms
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
Bristol-Myers Squibb (United States)
2023-2025
Molecular glues are small molecules that simultaneously bind to two proteins, creating a chemically induced protein–protein interface. CELMoDs (cereblon E3 ligase modulators) class of molecular promote recruitment neosubstrate proteins the ubiquitin cereblon (CRBN) for poly-Lys48-ubiquitination and proteasomal degradation. Ternary complex structures clinical CC-885 CC-90009 bound CRBN G1 S phase transition protein 1 (GSPT1) have been experimentally determined. Although cellular degradation...
Molecular glues enable the degradation of previously "undruggable" proteins via recruitment cereblon (CRBN) to target. One major challenge in designing CRBN E3 ligase modulating compounds (CELMoDs) is selectivity profile toward neosubstrates, recruited by agents for degradation. Common neosubstrates include Aiolos, Ikaros, GSPT1, CK1α, and SALL4. Unlike achieving potency traditional small molecule inhibitors, reducing these complicated ternary nature complex formed between protein, CRBN,...
The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp-mediated efflux an additional important target optimization. physicochemical properties most strongly associated with high and lower P-gp are size, polarity, lipophilicity. In this study, new metric called Balanced Permeability Index (BPI) was developed that combines these three properties. BPI found to be more...
Efficiency metrics are useful in medicinal chemistry to track small molecule progress lead optimization (LO). Molecular glue degraders molecules that mediate targeted protein degradation by chemically inducing proximity between an E3 ligase and a target. The potency depth of important factors identifying molecular drug candidates. We developed efficiency based on both objectives. applied these retrospectively clinical degrader series, resulting the identification Golcadomide (CC-99282). This...
Ligand-directed degraders (LDDs) are heterobifunctional molecules that degrade proteins by engaging the ubiquitin-protein ligase (E3) system. LDDs consist of a target-engaging moiety, an E3 ligase-binding moiety and bridging linker. Due to their size physicochemical complexity these do not adhere well-established rules lead optimization. The optimization passive permeability remains key challenge develop orally bioavailable LDDs. To overcome this challenge, in study we demonstrate Balanced...
Dual activation of the TLR7 and TLR8 pathways leads to production type I interferon proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells promote T-cell priming antitumor immunity. We developed a novel series TLR7/8 dual agonists with varying ratios activity for use as payloads an antibody–drug conjugate approach. The agonist-induced several cytokines human whole blood confirmed their functional activity. Structure–activity relationship studies guided...