9XZ1

KRAS(G12C)-RNK07311-HSP90(N-terminus)

This is a non-PDB format compatible entry.

Summary for 9XZ1

• Entry DOI: 10.2210/pdb9xz1/pdb
• Descriptor: Heat shock protein HSP 90-alpha, GTPase KRas, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (8 entities in total)
• Functional Keywords: kras hsp90 heterobifunctional inhibitor, chaperone, chaperone-oncoprotein complex, chaperone/oncoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 47736.05

Authors

Prince, T.L.,Wang, Y.,Ying, C.,Foley, K.P.,Ying, W. (deposition date: 2025-08-26, release date: 2025-10-15)

Primary citation

Pulido, I.,Luan, Q.,Pastor-Puente, S.,Gunder, L.,Wang, Y.,Ying, C.,Li, J.,Sun, Y.,Dai, Y.,Ascoli, C.,Abdelhady, K.,Massad, M.,Prince, T.L.,Wang, G.,Foley, K.P.,Ying, W.,Papautsky, I.,Carretero, J.,Shimamura, T.
Chaperone directed heterobifunctional molecules circumvent KRAS G12C inhibitor resistance.
Cancer Lett., 622:217691-217691, 2025

PubMed Abstract: While KRAS inhibitors have shown promising results in clinical activity, acquired resistance remains a significant barrier to durable responses. Combination therapies have been explored to improve the efficacy of KRAS inhibitors; however, their use is often restricted due to toxicity and limitations in clinically amenable dosing schedules. Transcriptomic profiling and functional assays on acquired resistant models to adagrasib identified an enrichment of HSP90 client proteins in resistant phenotypes, suggesting a therapeutic vulnerability. To address the finding, RNK07421, a novel heterobifunctional molecule, was developed to simultaneously target KRAS and HSP90-client oncoproteins. Structural and biochemical analyses demonstrated that RNK07421 disrupts KRAS interactions by inducing a non-natural interface with HSP90, thereby impairing oncogenic signaling. In vitro, RNK07421 effectively suppressed ERK reactivation and reduced viability in KRAS-mutant cell lines exhibiting either intrinsic or acquired resistance. In vivo, RNK07421 significantly reduced tumor burden in xenograft models, outperforming both monotherapies and combination therapies. These findings highlight dual KRAS and HSP90 inhibition as a promising strategy to overcome resistance in KRAS-driven cancers.

PubMed: 40204148
DOI: 10.1016/j.canlet.2025.217691

Experimental method

X-RAY DIFFRACTION (1.96 Å)