Carna Biosciences, Inc.’s Post

Our last paper has been published 🤞 If you are interested in tyrosine kinase inhibitors, you can access them from the link.

CADD (Computer-aided drug design) A POWERFUL TOOL FOR THE DEVELOPMENT OF KINASE INHIBITORS In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. These enzymes are involved in the regulation of various cellular processes such as growth, division, and metabolism. For this reason, kinases are a highly sought-after drug target in the pharmaceutical field. Kinase inhibitors are used to treat cancer and other diseases where abnormal kinase activity plays a key role. Designing inhibitors that are specific to one kinase requires considerable effort by medicinal chemists. CADD (Computer-aided drug design) has become a powerful tool in the development of kinase inhibitors. Not only CADD but also techniques such as molecular docking, pharmacophore modeling and virtual screening are part of the common effort in designing new kinase inhibitors. Thanks to these techniques, only in the last period - 2021-2023 - numerous kinase inhibitors have been developed and have reached FDA approval. Below are some kinase inhibitors discovered or developed with the help of CADD, and approved by FDA. #kinase #kinaseinhibitor #CADD

#FDA-approved kinase #inhibitors #discovered using the computer-aided #drug design strategy (2021–2023). #drugdesign #drugdiscovery #compchem #computationalchemistry #protacs Computer-aided drug design (CADD) has become a powerful tool in the development of kinase inhibitors, which are a class of drugs that target kinases, enzymes involved in the regulation of various cellular processes such as growth, division, and metabolism. Many of these inhibitors are used to treat cancer and other diseases where abnormal kinase activity plays a key role. Over the past few years, from 2021 to 2023, CADD has significantly contributed to the discovery and development of FDA-approved kinase inhibitors. These inhibitors are often identified through a combination of techniques like molecular docking, pharmacophore modeling, and virtual screening, which help in designing and optimizing compounds that can effectively interact with kinase targets. Here are some FDA-approved kinase inhibitors discovered or developed with the help of CADD during the period 2021–2023:

Our prodrug technology platform enables potentially greater control over the non-hematological side effects common to kinase inhibitor therapies, such as nausea or diarrhea, and it may improve drug delivery into the target tissue. Learn more: https://bit.ly/2ZLven4

Now available from 2BScientific Ltd. learn more about where Echelon’s PI4K Kinase related kits fit into your workflow, take a look at our full article here: https://lnkd.in/exQfwnfp Echelon Biosciences recognises the significance of investigating the involvement of PI4K in cellular signalling, as evidenced by the notable reagents they offer. 🐝 PI(4)P Mass ELISA Kit - Precisely quantifies PI(4)P with unmatched specificity. 🐝 PI4-Kinase Activity Assay - Essential for understanding membrane signaling by measuring PI(4)P levels. 🐝 Purified Anti-PtdIns(4)P Monoclonal Antibody - Highly specific for targeting PtdIns(4)P, aiding research on cell signaling. Our friendly team at 2BScientific Ltd. guarantees fast service and 100% product satisfaction, make sure to get in contact at sales@2bscientific.com with any queries about Echelons products, or anything concerning life science reagents! #oncology #proteomics #lipids #cancerresearch #cellbiology

MLCK Inhibitor Peptide 18 TFA, Inhibitor of Myosin Light Chain Kinase

Highlights the importance of taking biophysical properties into consideration in designing novel TKIs. FGFR2 specificity vs. FGFR1. Very cool findings in PNAS.

A great read on Medchem driven iterative SAR study, undertaking an optimization campaign, which effectively combined kinase selectivity, potency, & PK properties towards the discovery of compound 38 (BAY-405), which is a highly potent and selective inhibitor of MAP4K1 exhibiting favorable drug-like properties, achieving meaningful exposure in vivo, and capable of inducing potent antitumor T-cell immunity in vivo. Compared to 1, which displays a selectivity score 27 of S = 0.13 (80%, 1 μM) and inhibits several kinases more potently than MAP4K1, BAY-405 shows a significantly improved kinase selectivity score S = 0.080 (80%, 1 μM), with MAP4K1 representing the most potently inhibited kinase. Furthermore, excellent drug-like properties of BAY-405 allowed it to be evaluated orally across a range of preclinical species. The X-raystructure ofBAY-405 in complex with the kinase domain of human MAP4K1 shows an ATP-competitive binding mode, with the pyrrolopyridine anchoring the molecule to the hinge region via two classical H- bonds. The trifluoromethyl-cyclopropyl moiety sits smoothly in the; back pocket of the kinase, which remains in a DFG-inconformation. The central fluorinated phenyl ring (A-ring) is arranged perpendicular to the hinge binding heterocycle,with, the conformation being stabilized by the o,o-disubstitution. The tip of the nucleotide binding loop folds back into the pocket, allowing for a π−π-stacking interaction of the A-ring with the side chain of Tyr28.While the oxazine moiety engages in a bidentate H-bond with the Asp101 carboxylic acid, the terminal tetrahydropyran ring in the spiro-ring system does not show any direct interactions with the crystallized kinase domain. https://lnkd.in/gUk4Y7NG

The Journey of p38 MAP Kinase Inhibitors: From Bench to Bedside in Treating Inflammatory Diseases The review traces the evolution of p38 MAP kinase inhibitors from initial laboratory studies to clinical candidates, with a focus on the optimization processes of representative p38 MAPK inhibitors in various clinical trials while emphasizing on how lead compounds are modified to improve efficacy, selectivity, and pharmacokinetic properties. This detailed exploration of the optimization process will provide valuable insights for future research and development of p38 MAPK inhibitors to significantly alter the treatment approach for inflammatory diseases. https://lnkd.in/gKuBtEmc

Targeting PD-L1 with peptide-coated mRNA-LNPs: Sun Hwa Kim, Yoosoo Yang and collaborators at KIST(Korea Institute of Science and Technology) developed an efficient approach to integrate tumor-targeting peptides into lipid nanoparticles. The PD-L1 binding peptides are linked to PEGylated lipids using a copper-free click reaction and directly integrated into the LNP formulation https://lnkd.in/e77K-RqE They observed that these LNPs loaded with  mRNA encoding phosphatase and tensin homolog specifically induce autophagy-mediated immunogenic cell death in 4T1 tumors, leading to robust anticancer immune responses. An article also authored by Yelee Kim, Jiwoong Choi, Eun Hye Kim, Wonbeom Park, Hochung Jang, Yeongji Jang, 지성길Sung-Gil Chi, Dae-Hyuk Kweon and Kyuri Lee #LNP #drugdelivery #formulation #nanomedicine #cancerresearch #Vesiculab