2. Academic Validation
  3. Discovery of novel indoline derivatives as potent small molecule PD-L1 inhibitors

Discovery of novel indoline derivatives as potent small molecule PD-L1 inhibitors

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130458. doi: 10.1016/j.bmcl.2025.130458.
Deok-Mo Yang 1,  Yeo Wool Kang 2,  Kwonwoo Kim 2,  Suk-Ho Lee 2,  Taegwon Oh 2,  Kye Jung Shin 3,  Myung Jin Kim 2,  Tae-Hwe Heo 4,  Ikyon Kim 5
Affiliations

Affiliations

  • 1 Research Institute, ILAb Co., Ltd., 804ho, 9-22, Pangyo-ro 255beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea; College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
  • 2 Research Institute, ILAb Co., Ltd., 804ho, 9-22, Pangyo-ro 255beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.
  • 3 College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
  • 4 Integrated Research Institute of Pharmaceutical Sciences, BK21 PLUS Team for Creative Leader Program for Pharma Comics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Republic of Korea. Electronic address: [email protected].
  • 5 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea. Electronic address: [email protected].
PMID: 41183622 DOI: 10.1016/j.bmcl.2025.130458
Abstract

The immune system plays a critical role in Cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade have shown remarkable success in reactivating T-cell function in various advanced cancers, but they face limitations such as long half-life and immune-related adverse events (irAEs). In this study, we identified a new class of indoline-based scaffold through molecular docking analysis and synthesized derivatives, identifying compound 31 with an IC50 of 0.89 nM in FRET assay. Compound 31 showed less than 50 % inhibition against CYP and hERG, and demonstrated moderate liver microsomal stability in mice. These results suggest that indoline derivatives may serve as potential PD-L1 inhibitors and warrant further investigation.

Keywords

Internalization of PD-L1; Molecular docking; Novel indoline derivatives; Small molecule PD-L1 inhibitors.

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