9D0X

Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4 (local mask)

これはPDB形式変換不可エントリーです。

9D0X の概要

• エントリーDOI: 10.2210/pdb9d0x/pdb
• 関連するPDBエントリー: 9D0W
• EMDBエントリー: 46464 46465
• 分子名称: Protein cereblon, Cyclin-dependent kinase 2, G1/S-specific cyclin-E1, ... (5 entities in total)
• 機能のキーワード: kinase, degrader, ternary complex, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 114607.87

構造登録者

Kwiatkowski, N.,Liang, T.,Sha, Z.,Collier, P.N.,Yang, A.,Sathappa, M.,Paul, A.,Su, L.,Zheng, X.,Aversa, R.,Li, K.,Mehovic, R.,Breitkopf, S.B.,Chen, D.,Howarth, C.L.,Yuan, K.,Jo, H.,Growney, J.D.,Weiss, M.,Williams, J. (登録日: 2024-08-07, 公開日: 2025-04-16, 最終更新日: 2025-04-30)

主引用文献

Kwiatkowski, N.,Liang, T.,Sha, Z.,Collier, P.N.,Yang, A.,Sathappa, M.,Paul, A.,Su, L.,Zheng, X.,Aversa, R.,Li, K.,Mehovic, R.,Kolodzy, C.,Breitkopf, S.B.,Chen, D.,Howarth, C.L.,Yuan, K.,Jo, H.,Growney, J.D.,Weiss, M.,Williams, J.
CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers.
Cell Chem Biol, 32:556-569.e24, 2025

PubMed Abstract: CCNE1 amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with high selectivity for CDK2 over CDK1 that also unexpectedly led to cyclin E1 degradation and potent and complete suppression of RB phosphorylation at concentrations with low CDK2 occupancy and negligible CDK1 degradation. Co-depletion of CDK2 and cyclin E1 also resensitized palbociclib-adapted breast cancer cells to cell cycle blockade. Overall, the improved potency and selectivity of the degrader for CDK2 over small-molecule inhibitors drives antiproliferative activity with greater specificity for CCNE1 cancer cells and RB dependency. Using an orally administered degrader, we demonstrate deep and sustained RB pathway suppression, which is needed to induce stasis in CCNE1 tumors. These results highlight the potential of this modality to target CDK2 potently and selectivity in this biomarker-defined patient population with high unmet need.

PubMed: 40250405
DOI: 10.1016/j.chembiol.2025.03.006

実験手法

ELECTRON MICROSCOPY (2.84 Å)