Allosteric p97 Inhibitors Can Overcome Resistance to ATP‐Competitive p97 Inhibitors for Potential Anticancer Therapy
Sign Up to like & getrecommendations! Published in 2020 at "ChemMedChem"
DOI: 10.1002/cmdc.201900722
Abstract: Abstract: A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target… read more here.
Keywords: p97 inhibitors; allosteric p97; atp competitive; competitive p97 ... See more keywords
Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.
Sign Up to like & getrecommendations! Published in 2022 at "Journal of medicinal chemistry"
DOI: 10.1021/acs.jmedchem.1c02192
Abstract: Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from… read more here.
Keywords: selective mek1; inhibitor; mek1 inhibitor; atp competitive ... See more keywords
Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor.
Sign Up to like & getrecommendations! Published in 2017 at "ACS chemical biology"
DOI: 10.1021/acschembio.7b00116
Abstract: PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor but it also causes selective reduction of endogenous JAK2… read more here.
Keywords: atp competitive; jak2 jak3; pan jak; jak2 ... See more keywords
Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands
Sign Up to like & getrecommendations! Published in 2020 at "Nature Communications"
DOI: 10.1038/s41467-020-19974-5
Abstract: Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins… read more here.
Keywords: kinase front; kinase; atp competitive; rnase ... See more keywords
Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
Sign Up to like & getrecommendations! Published in 2022 at "Nature communications"
DOI: 10.1038/s41467-022-29655-0
Abstract: The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development… read more here.
Keywords: allosteric atp; resistance; atp competitive; akt inhibitors ... See more keywords
Inhibitors in AKTion: ATP-competitive vs allosteric
Sign Up to like & getrecommendations! Published in 2020 at "Biochemical Society Transactions"
DOI: 10.1042/bst20190777
Abstract: Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target.… read more here.
Keywords: atp competitive; inhibitors aktion; aktion atp; competitive allosteric ... See more keywords
A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Sign Up to like & getrecommendations! Published in 2019 at "Annals of Oncology"
DOI: 10.1093/annonc/mdz268.085
Abstract: Abstract Background A subgroup of MEK1 mutations in human tumors were recently described as RAF- and phosphorylation independent and as insensitive to currently clinically used allosteric MEK inhibitors. We established a novel cell line that… read more here.
Keywords: inhibitor; mek inhibitor; atp competitive; mek ... See more keywords
ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy
Sign Up to like & getrecommendations! Published in 2022 at "Science Advances"
DOI: 10.1126/sciadv.abo0696
Abstract: ATP-competitive inhibitors are currently the largest class of clinically approved drugs for protein kinases. By targeting the ATP-binding pocket, these compounds block the catalytic activity, preventing substrate phosphorylation. A problem with these drugs, however, is… read more here.
Keywords: binding cooperativity; competitive inhibitors; conformational entropy; substrate binding ... See more keywords
Abstract 6489: Paradoxical activation of kinases occurs directly with ATP-competitive kinase inhibitors and is observable biochemically at physiologically relevant drug concentrations
Sign Up to like & getrecommendations! Published in 2024 at "Cancer Research"
DOI: 10.1158/1538-7445.am2024-6489
Abstract: We sought to screen all FDA approved, cancer-indicated, kinase targeting drugs using the gold standard radiometric biochemical activity assay (HotSpot) against the largest collection of kinases in the world (>100 drugs against 735 total kinases… read more here.
Keywords: atp competitive; kinase; activation; competitive kinase ... See more keywords
A phase II randomised study to evaluate the antitumour activity of roginolisib, a novel non-ATP competitive and allosteric modulator inhibiting PI3Kδ, in patients with metastatic uveal melanoma (OCULE-01).
Sign Up to like & getrecommendations! Published in 2025 at "Journal of Clinical Oncology"
DOI: 10.1200/jco.2025.43.16_suppl.tps9613
Abstract: TPS9613 Background: Uveal melanoma (UM) is a rare malignancy that develops from melanocytes in the eye. At least half of the patients develop metastases, primarily in the liver, and survival outcome from the time of… read more here.
Keywords: uveal melanoma; atp competitive; non atp; roginolisib ... See more keywords
On the development of B-Raf inhibitors acting through innovative mechanisms
Sign Up to like & getrecommendations! Published in 2022 at "F1000Research"
DOI: 10.12688/f1000research.108761.2
Abstract: B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In… read more here.
Keywords: innovative mechanisms; competitive inhibitors; raf; raf inhibitors ... See more keywords