7ZPC

CDK2 in complex 9K-DOS

7ZPC の概要

• エントリーDOI: 10.2210/pdb7zpc/pdb
• 分子名称: Cyclin-dependent kinase 2, ~{N}-(1-methylpyrazol-4-yl)-5-phenyl-pyrazolo[1,5-a]pyrimidine-7-carboxamide (3 entities in total)
• 機能のキーワード: cdk2, dos, med chem, inhibitor, cell cycle
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35079.68

構造登録者

Watt, J.E.,Martin, M.P.,Noble, M.E.N. (登録日: 2022-04-27, 公開日: 2023-02-01, 最終更新日: 2024-02-07)

主引用文献

Uguen, M.,Davison, G.,Sprenger, L.J.,Hunter, J.H.,Martin, M.P.,Turberville, S.,Watt, J.E.,Golding, B.T.,Noble, M.E.M.,Stewart, H.L.,Waring, M.J.
Build-Couple-Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity.
J.Med.Chem., 65:11322-11339, 2022

PubMed Abstract: High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a "build-couple-transform" paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build-couple-transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.

PubMed: 35943172
DOI: 10.1021/acs.jmedchem.2c00897

実験手法

X-RAY DIFFRACTION (1.4 Å)