Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	6	2022 Jun 02	1482-1499	Cancer Discov

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 149 PD-L1 Inhibitor 14	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	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
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