SMARCA2 PROTACとシクロデキストリンのコンフォメーション依存性複合体形成相互作用
Matthew N O'Brien Laramy1, José G Napolitano1, Yuhui Zhou2
1Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Molecular pharmaceutics
|December 20, 2025
まとめ
タンパク質分解因子または標的タンパク質分解キメラ(PROTAC)は、溶解度に影響を与える独自のコンフォメーション特性を示します。これらのPROTACコンフォメーションを理解することは、効果的な製剤および薬剤開発の鍵となります。
科学分野:
- 生化学
- 医薬品化学
- 製剤科学
背景:
- 標的タンパク質分解キメラ(PROTAC)として知られる二価タンパク質分解因子は、新規の治療アプローチを表す。
- PROTACは、溶解度のような生物製剤学的特性を妨げる可能性のある独自の物理化学的および構造的特性を持っており、薬剤開発を複雑にする。
- これらの課題に対処するために特別に調整されたPROTACの製剤戦略に関する研究は限られている。
主な方法:
- 核磁気共鳴(NMR)分光法技術を利用した。
- 等温滴定熱量測定(ITC)を採用した。
- 定量的な溶解度測定を実施した。
結論:
- コンフォメーションと立体化学は、PROTACの合理的な製剤設計において、これまで報告されていない重要な役割を果たしている。
- PROTACの明確なコンフォメーション集団は、HP-β-CDのような可溶化添加剤に対して異なる応答を示す。
- これらの発見は、溶解度を高めるためにVHLベースのPROTACを製剤化するための具体的な考慮事項を提供する。
関連する概念動画
Complexation Equilibria: The Chelate Effect
1.1K
In complexation reactions, metal atoms or cations interact with ligands to form donor-acceptor adducts called metal complexes. Ligands that bind through one donor site are monodentate, ligands with two donor sites are bidentate, and those with more than two donor sites are polydentate ligands. For example, ethylene diamine is a bidentate ligand that binds through two nitrogen donor atoms, forming a five-membered ring. EDTA is a polydentate ligand that binds through four oxygen and two nitrogen...
1.1K
Assembly of Signaling Complexes
6.4K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.4K
Complexation Equilibria: Factors Influencing Stability of Complexes
761
In complexation reactions, metal cations are the electron pair acceptors, and the ligands are the electron pair donors. The stability of the metal complexes depends primarily on the complexing ability of the central metal ion and the nature of the ligands. Generally, the complexing ability of the metal ion depends on the size and charge of the ion. As the metal ion size increases, the stability of the metal complexes decreases, provided that the valency of the metal ion and the ligands remain...
761
Formation of Complex Ions
25.5K
A type of Lewis acid-base chemistry involves the formation of a complex ion (or a coordination complex) comprising a central atom, typically a transition metal cation, surrounded by ions or molecules called ligands. These ligands can be neutral molecules like H2O or NH3, or ions such as CN− or OH−. Often, the ligands act as Lewis bases, donating a pair of electrons to the central atom. These types of Lewis acid-base reactions are examples of a broad subdiscipline called coordination...
25.5K
Complexation Equilibria: Overview
1.3K
Complexation reactions take place when dative or coordinate covalent bonds form between metal ions and ligands. The compounds formed in these reactions are called coordination compounds. The number of bonds formed between the metal ion and the ligands is called its coordination number. Generally, most metal ions in an aqueous solution are solvated by water molecules and thus exist as aqua complexes.
The equilibrium constant of the complexation reaction is represented as the formation constant...
The equilibrium constant of the complexation reaction is represented as the formation constant...
1.3K
Complexometric Titration: Ligands
2.2K
Different monodentate and polydentate ligands are used as complexing agents in complexometric titration reactions. The formation of complexes by mono- and bidentate ligands involves two or more intermediate steps, limiting their use as complexing agents. In comparison, polydentate ligands can form complexes with metal ions in a single-step process, facilitating sharper end points. This means polydentate ligands, such as amino carboxylic acid derivatives, are most commonly employed in...
2.2K


