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-Structure paper
タイトル | The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers. |
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ジャーナル・号・ページ | Cancer Discov, Vol. 14, Issue 7, Page 1190-1205, Year 2024 |
掲載日 | 2024年7月1日 |
著者 | Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Ayşegül Özen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel / |
PubMed 要旨 | Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the ...Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor. |
リンク | Cancer Discov / PubMed:38588399 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.07 - 4.36 Å |
構造データ | EMDB-43931, PDB-9axa: EMDB-43932, PDB-9axc: PDB-9axh: PDB-9axm: PDB-9axx: PDB-9axy: PDB-9ay7: PDB-9aya: |
化合物 | PDB-1ahe: ChemComp-ANP: ChemComp-MG: ChemComp-EDO: ChemComp-CL: ChemComp-HOH: ChemComp-GOL: ChemComp-TRS: ChemComp-NI: ChemComp-ACT: |
由来 |
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キーワード | TRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN |