2. Academic Validation
  3. Rational design, optimization, and biological evaluation of novel pyrrolo-pyridone derivatives as potent and orally active Cbl-b inhibitors

Rational design, optimization, and biological evaluation of novel pyrrolo-pyridone derivatives as potent and orally active Cbl-b inhibitors

  • Eur J Med Chem. 2025 Jun 5:290:117488. doi: 10.1016/j.ejmech.2025.117488.
Yixuan Zhang 1,  Xiangna Guan 2,  Yushuang Chai 3,  Tingting Lu 3,  Na An 3,  Xinyu Lin 4,  Xuebin Liao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, 100084, China; School of Pharmacy, Bengbu Medical University, Bengbu, 233030, China.
  • 2 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 3 Zhuhai Yufan Biotechnologies Co., Ltd, Zhuhai, Guangdong, China.
  • 4 Zhuhai Yufan Biotechnologies Co., Ltd, Zhuhai, Guangdong, China. Electronic address: xingyu.lin@yufanbj.com.
  • 5 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: liaoxuebin@mail.tsinghua.edu.cn.
PMID: 40120499 DOI: 10.1016/j.ejmech.2025.117488
Abstract

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, plays a critical role in negatively regulating T-cell, natural killer (NK) cell, and B-cell activation. Inhibiting Cbl-b has emerged as a promising immuno-oncology strategy to enhance immune cell function. Here, we describe the rational design and optimization of pyrrolo-pyridone derivatives as potent Cbl-b inhibitors. Using structure-based drug design, we identified key structural elements that enhance binding affinity and inhibitory potency. Notably, compound B2 stands out, showing superior potency in stimulating IL-2 production in T cells and modulating phosphorylation of key proteins in T-cell receptor signaling. Furthermore, B2 demonstrates favorable pharmacokinetics and significantly inhibits tumor growth in vivo, outperforming NX-1607, which is currently in clinical trials.

Keywords

Cancer immunotherapy; Cbl-b inhibitors; Immune checkpoint blockade; Pyrrolo-pyridone derivatives; Structure-activity relationship (SAR).

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