Drug resistance is a major problem often limiting the long-term effectiveness of targeted cancer therapeutics. Resistance can be acquired through mutations or amplification of the primary drug targets or activation of bypass signaling pathways. Considering the multifaceted function of WDR5 in human malignancies, WDR5 has emerged as an attractive drug target for the discovery of small-molecule inhibitors. In this study, we investigated if cancer cells might develop resistance to a highly potent WDR5 inhibitor. We established a drug-adapted cancer cell line and discovered that WDR5 mutation occurs in the resistant cells, which confers resistance by preventing target engagement of the inhibitor. This work elucidated the WDR5 inhibitor's potential resistance mechanism in a preclinical study as a reference for future study in the clinical stage.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.3c00108DOI Listing

Publication Analysis

Top Keywords

wdr5 inhibitor
8
wdr5
6
resistance
5
mechanism resistance
4
resistance wdr5
4
inhibitor mll-rearranged
4
mll-rearranged leukemia
4
leukemia drug
4
drug resistance
4
resistance major
4

Similar Publications

Catalytic-independent functions of the Integrator-PP2A complex (INTAC) confer sensitivity to BET inhibition.

Nat Chem Biol

January 2025

Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription-activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs, with poorly understood mechanisms. Here, using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary/arm/tail module of the Integrator-PP2A complex (INTAC), a global regulator of RNA polymerase II pause-release dynamics.

View Article and Find Full Text PDF

Discovery of WDR5-MLL1 and HDAC Dual-Target Inhibitors for the Treatment of Acute Myeloid Leukemia.

J Med Chem

January 2025

Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Targeting the WDR5-MLL1 protein-protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5-MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5-MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells.

View Article and Find Full Text PDF

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis and limited options for targeted therapies. Identifying new molecular targets to develop novel therapeutic strategies is the pressing immediate issue in T-ALL. Here, we observed high expression of WD Repeat-Containing Protein 5 (WDR5) in T-ALL; with in vitro and in vivo models we demonstrated the oncogenic role of WDR5 in T-ALL by activating cell cycle signaling through its new downstream effector, ATPase family AAA domain-containing 2 (ATAD2).

View Article and Find Full Text PDF

WD repeat domain 5 (WDR5) inhibitors: a patent review (2016-present).

Expert Opin Ther Pat

January 2025

Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Introduction: WDR5 is an epigenetic scaffolding protein that has attracted significant interest as an anti-cancer drug target, especially in MLL-rearranged leukemias. The most druggable 'WIN-site' on WDR5, which tethers WDR5 to chromatin, has been successfully targeted with multiple classes of exquisitely potent small-molecule protein-protein interaction inhibitors. Earlier progress has also been made on the development of WDR5 degraders and inhibitors at the 'WBM-site' on the opposite face of WDR5.

View Article and Find Full Text PDF

The E3 ubiquitin ligase RNF220 maintains hindbrain expression patterns through regulation of WDR5 stability.

Elife

November 2024

Key Laboratory of Genetic Evolution and Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.

The spatial and temporal linear expression of genes establishes a regional code, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural development via targeting of multiple substrates. Here, we found that the expression of genes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!