2. Academic Validation
  3. Serial PNA-Transformer-Based Virtual Screening Identifies Nanomolar DYRK1A Inhibitors for Pancreatic Ductal Adenocarcinoma

Serial PNA-Transformer-Based Virtual Screening Identifies Nanomolar DYRK1A Inhibitors for Pancreatic Ductal Adenocarcinoma

  • ACS Med Chem Lett. 2026 Feb 20;17(3):695-703. doi: 10.1021/acsmedchemlett.5c00723.
Hongyu Zhang 1,  Ke Wang 2,  Xiaochuan Wu 3,  Rui Zhou 2,  Chaofeng Li 4,  Xiuyu Cai 5,  Yanyan Zhuang 2
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
  • 3 State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 4 Guangdong Provincial Clinical Research Center for Cancer, State Key Laboratory of Oncology in South China, Department of Information Technology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 5 Guangdong Provincial Clinical Research Center for Cancer, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
PMID: 41847637 DOI: 10.1021/acsmedchemlett.5c00723
Abstract

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is a promising therapeutic target for pancreatic ductal adenocarcinoma (PDAC). Herein, we developed an integrated AI and structure-based pipeline featuring a Serial PNA-Transformer graph neural network, which achieved a test AUC of 0.8901. Multistage screening of 21,738 compounds prioritized 232 candidates across 10 chemical clusters. Enzymatic assays confirmed three hits with IC50 values <500 nM; notably, CX-6258 (IC50 = 473.7 nM) exhibited potent antiproliferative activity in MIA PaCa-2 and Panc-1 cell lines with low micromolar potencies (IC50 = 0.679 and 1.148 μM, respectively). Selectivity profiling confirmed the potency of CX-6258 against DYRK1A/B with a favorable window over Other CMGC kinases. Crucially, siRNA-mediated knockdown and overexpression assays demonstrated that its cytotoxicity is strictly DYRK1A-dependent. Molecular dynamics revealed a stable binding mode characterized by a unique Arg250-mediated electrostatic driving force. These findings underscore the utility of our AI-driven framework in accelerating the identification and mechanistic validation of potent therapeutic leads.

Keywords

DYRK1A; graph neural network; molecular dynamics; pancreatic ductal adenocarcinoma; virtual screening.

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