EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.
ジャーナル・号・ページ	Cancer Discov, Vol. 14, Issue 2, Page 240-257, Year 2024
掲載日	2024年2月8日
著者	Andreas Varkaris / Ermira Pazolli / Hakan Gunaydin / Qi Wang / Levi Pierce / Alessandro A Boezio / Artemisa Bulku / Lucian DiPietro / Cary Fridrich / Adam Frost / Fabrizio Giordanetto / Erika P Hamilton / Katherine Harris / Michael Holliday / Tamieka L Hunter / Amanda Iskandar / Yongli Ji / Alexandre Larivée / Jonathan R LaRochelle / André Lescarbeau / Fabien Llambi / Brenda Lormil / Mary M Mader / Brenton G Mar / Iain Martin / Thomas H McLean / Klaus Michelsen / Yakov Pechersky / Erika Puente-Poushnejad / Kevin Raynor / Dipali Rogala / Ramin Samadani / Alison M Schram / Kelley Shortsleeves / Sweta Swaminathan / Shahein Tajmir / Gege Tan / Yong Tang / Roberto Valverde / Bryan Wehrenberg / Jeremy Wilbur / Bret R Williams / Hongtao Zeng / Hanmo Zhang / W Patrick Walters / Beni B Wolf / David E Shaw / Donald A Bergstrom / James Watters / James S Fraser / Pascal D Fortin / D Randal Kipp /
PubMed 要旨	PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. ...PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.
リンク	Cancer Discov / PubMed:37916956 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	2.51 - 3.62 Å
構造データ	41617 8tu6 EMDB-41617, PDB-8tu6: CryoEM structure of PI3Kalpha 手法: EM (単粒子) / 解像度: 3.12 Å PDB-8ts7: Human PI3K p85alpha/p110alpha 手法: X-RAY DIFFRACTION / 解像度: 2.71 Å PDB-8ts8: p85alpha/p110alpha heterodimer H1047R mutant 手法: X-RAY DIFFRACTION / 解像度: 2.72 Å PDB-8ts9: Human PI3K p85alpha/p110alpha H1047R bound to compound 1 手法: X-RAY DIFFRACTION / 解像度: 2.83 Å PDB-8tsa: Human PI3K p85alpha/p110alpha H1047R bound to compound 2 手法: X-RAY DIFFRACTION / 解像度: 2.51 Å PDB-8tsb: Human PI3K p85alpha/p110alpha bound to compound 2 手法: X-RAY DIFFRACTION / 解像度: 3.53 Å PDB-8tsc: Human PI3K p85alpha/p110alpha H1047R bound to compound 3 手法: X-RAY DIFFRACTION / 解像度: 3.62 Å PDB-8tsd: Human PI3K p85alpha/p110alpha bound to RLY-2608 手法: X-RAY DIFFRACTION / 解像度: 2.7 Å
化合物	ChemComp-UE9: 5-[3-fluoro-5-(trifluoromethyl)benzamido]-N-methyl-6-(2-methylanilino)pyridine-3-carboxamide ChemComp-UIW: 5-(3-bromo-5-fluorobenzamido)-N-methyl-6-(2-methylanilino)pyridine-3-carboxamide ChemComp-UJC: (1S)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-N-methyl-1-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindole-5-carboxamide ChemComp-XUZ: N-{(3R,6M)-3-(2-chloro-5-fluorophenyl)-6-[(4S)-5-cyano[1,2,4]triazolo[1,5-a]pyridin-6-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-3-fluoro-5-(trifluoromethyl)benzamide
由来	homo sapiens (ヒト)
キーワード	SIGNALING PROTEIN / Lipid kinase (キナーゼ) / SIGNALING PROTEIN/INHIBITOR / SIGNALING PROTEIN-INHIBITOR complex / TRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR complex / CYTOSOLIC PROTEIN (細胞質基質) / PI3Kalapha / isoform selective / structure-based drug design. (医薬品設計)