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Ref Type Journal Article
PMID (35254416)
Authors Koblish HK, Wu L, Wang LS, Liu PCC, Wynn R, Rios-Doria J, Spitz S, Liu H, Volgina A, Zolotarjova N, Kapilashrami K, Behshad E, Covington M, Yang YO, Li J, Diamond S, Soloviev M, O'Hayer K, Rubin S, Kanellopoulou C, Yang G, Rupar M, DiMatteo D, Lin L, Stevens C, Zhang Y, Thekkat P, Geschwindt R, Marando C, Yeleswaram S, Jackson J, Scherle P, Huber R, Yao W, Hollis G
Title Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor.
URL
Abstract Text 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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
INCB086550 INCB086550 2 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
INCB086550 INCB 086550|INCB-086550 Immune Checkpoint Inhibitor 147 PD-L1 Inhibitor 13 INCB086550 is a small molecule PD-L1 (CD274) inhibitor that prevents PD-L1/PD-1 interaction, potentially leading to enhanced anti-tumor immune response (PMID: 35254416).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CD274 over exp breast cancer sensitive INCB086550 Preclinical - Cell line xenograft Actionable In a preclinical study, INCB086550 decreased CD274 (PD-L1) surface expression and tumor growth in a cell line xenograft model of breast cancer with high CD274 (PD-L1) expression (PMID: 35254416). 35254416
CD274 over exp colorectal cancer sensitive INCB086550 Preclinical Actionable In a preclinical study, INCB086550 decreased CD274 (PD-L1) cell surface expression and inhibited tumor growth in a mouse model of colorectal cancer with CD274 (PD-L1) overexpression (PMID: 35254416). 35254416