2. Academic Validation
  3. Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

  • Cancer Discov. 2022 Jun 2;12(6):1482-1499. doi: 10.1158/2159-8290.CD-21-1156.
Holly K Koblish # 1,  Liangxing Wu # 1,  Liang-Chuan S Wang # 1,  Phillip C C Liu 1,  Richard Wynn 1,  Jonathan Rios-Doria 1,  Susan Spitz 1,  Hao Liu 1,  Alla Volgina 1,  Nina Zolotarjova 1,  Kanishk Kapilashrami 1,  Elham Behshad 1,  Maryanne Covington 1,  Yan-Ou Yang 1,  Jingwei Li 1,  Sharon Diamond 1,  Maxim Soloviev 1,  Kevin O'Hayer 1,  Stephen Rubin 1,  Chrysi Kanellopoulou 1,  Gengjie Yang 1,  Mark Rupar 1,  Darlise DiMatteo 1,  Luping Lin 1,  Christina Stevens 1,  Yue Zhang 1,  Pramod Thekkat 1,  Ryan Geschwindt 1,  Cindy Marando 1,  Swamy Yeleswaram 1,  Jeff Jackson 1,  Peggy Scherle 1,  Reid Huber 1,  Wenqing Yao 1,  Gregory Hollis 1
Affiliations

Affiliation

  • 1 Incyte Research Institute, Wilmington, DE.
  • # Contributed equally.
PMID: 35254416 DOI: 10.1158/2159-8290.CD-21-1156
Abstract

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic Antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with Antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies.

Significance: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal Antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397.

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