CD274

Summary

CD274 (CD274 molecule, HGNC:17635) is a protein-coding gene on chromosome 9p24.1, encoding Programmed cell death 1 ligand 1 (Q9NZQ7). Plays a critical role in induction and maintenance of immune tolerance to self. In precision oncology, CD274 Expression confers sensitivity to Atezolizumab in Lung Non-small Cell Carcinoma (CIViC Level B); 11 further curated variant–drug associations are listed below.

This gene encodes an immune inhibitory receptor ligand that is expressed by hematopoietic and non-hematopoietic cells, such as T cells and B cells and various types of tumor cells. The encoded protein is a type I transmembrane protein that has immunoglobulin V-like and C-like domains. Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. During infection or inflammation of normal tissue, this interaction is important for preventing autoimmunity by maintaining homeostasis of the immune response. In tumor microenvironments, this interaction provides an immune escape for tumor cells through cytotoxic T-cell inactivation. Expression of this gene in tumor cells is considered to be prognostic in many types of human malignancies, including colon cancer and renal cell carcinoma. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 29126 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neonatal diabetes mellitus (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 30 total — 6 pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 12 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_014143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17635
Approved symbol	CD274
Name	CD274 molecule
Location	9p24.1
Locus type	gene with protein product
Status	Approved
Aliases	B7-H, B7H1, PD-L1, PDL1, B7-H1
Ensembl gene	ENSG00000120217
Ensembl biotype	protein_coding
OMIM	605402
Entrez	29126

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000381573, ENST00000381577, ENST00000474218, ENST00000492923, ENST00000498261

RefSeq mRNA: 2 — MANE Select: NM_014143 NM_001267706, NM_014143

CCDS: CCDS59118, CCDS6464

Canonical transcript exons

ENST00000381577 — 7 exons

Exon	Start	End
ENSE00000813155	5456100	5456165
ENSE00000813157	5462834	5463121
ENSE00000813158	5465499	5465606
ENSE00001889081	5467840	5470554
ENSE00001892659	5450542	5450596
ENSE00003507383	5466770	5466829
ENSE00003541119	5457079	5457420

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 88.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7683 / max 968.8898, expressed in 1121 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95944	18.7683	1121

Top tissues by expression

245 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	88.56	gold quality
placenta	UBERON:0001987	86.83	gold quality
lower lobe of lung	UBERON:0008949	86.80	gold quality
epithelial cell of pancreas	CL:0000083	86.75	gold quality
upper lobe of left lung	UBERON:0008952	85.84	gold quality
upper lobe of lung	UBERON:0008948	85.72	gold quality
right lung	UBERON:0002167	84.89	gold quality
left ventricle myocardium	UBERON:0006566	84.81	gold quality
vermiform appendix	UBERON:0001154	83.83	gold quality
pancreatic ductal cell	CL:0002079	83.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.44	gold quality
lung	UBERON:0002048	82.26	gold quality
heart right ventricle	UBERON:0002080	82.22	gold quality
myocardium	UBERON:0002349	81.56	gold quality
heart left ventricle	UBERON:0002084	81.30	gold quality
spleen	UBERON:0002106	81.26	gold quality
cardiac ventricle	UBERON:0002082	81.01	gold quality
ileal mucosa	UBERON:0000331	79.96	gold quality
heart	UBERON:0000948	77.79	gold quality
lymph node	UBERON:0000029	77.40	gold quality
tibialis anterior	UBERON:0001385	77.12	silver quality
apex of heart	UBERON:0002098	76.82	gold quality
blood	UBERON:0000178	76.43	gold quality
right atrium auricular region	UBERON:0006631	76.40	gold quality
thymus	UBERON:0002370	76.35	gold quality
cardiac atrium	UBERON:0002081	76.04	gold quality
stromal cell of endometrium	CL:0002255	75.58	gold quality
caecum	UBERON:0001153	75.53	gold quality
deltoid	UBERON:0001476	75.35	silver quality
gall bladder	UBERON:0002110	75.04	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.14
E-MTAB-8498	yes	10.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA1, HIF1A, IRF1, KMT2C, NFKB, STAT1, STAT3

miRNA regulators (miRDB)

141 targeting CD274, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro (PMID:12091876)
• B7-H1 is inducible on human endothelial cells by IFN-gamma both in vitro and in vivo; blocking its interaction with its receptor (PD-1) on T cells augments T cell cytokine synthesis. (PMID:12244148)
• up-regulation in HIV infection, relation to disease progression, and possible role in AIDS progression (PMID:12468426)
• Blockade of PD-L1 during T cell responses initiated by allogenic dendritic cells increases T cell proliferation and cytokine production, showing that PD-L1 functions to inhibit T cell activation. (PMID:12538684)
• Monoclonal antibody DF272-defined surface molecule B7-H1 represents a unique receptor structure on dendritic cells that may play a role in the induction and maintenance of T cell anergy. (PMID:12646628)
• binding properties of B7-H1 to programmed death-1. (PMID:12893276)
• B7-H1 is expressed in muscle cells and may have a negative immune regulatory function in idiopathic inflammatory myopathies. (PMID:12923066)
• review of the negative immunoregulatory role of B7-H1 documented in human diseases, including cancer and auotimmune diseases (PMID:14686489)
• Inflammatory bowel disease intestinal epithelial cell (IEC) surface expressed B7h and B7-H1. Proliferation of IEC-stimulated T cells was inhibited only by B7h immunoglobulin. Interferon gamma was inhibited by both anti-B7h mAb and B7h Ig. (PMID:15131796)
• B7-H1 may have a role in antitumor immune responses in non-small cell lung cancer (PMID:15297412)
• IFN-beta up-regulates B7-H1 in vitro and in MS patients in vivo and might represent a novel mechanism how IFN-beta acts as a negative modulator on APC T-cell interactions in the periphery. (PMID:15342209)
• Data suggest that PD-L1 status may be a new predictor of prognosis for patients with esophageal cancer. (PMID:15837746)
• B7 homolog 1 (B7H1) may be involved in the immune evasion of human glioma (PMID:15973152)
• Inhibitory signals delivered from human rhinovirus HRV14-treated dendritic cells to T cells via B7-H1 are critical for induction of T-cell anergy. (PMID:16002716)
• dermal fibroblasts express the B7-H1 mRNA in the process of skin inflammation, suggesting the involvement of NF-kappaB and MAPK and PI3K (PMID:16085391)
• Interaction of tubular epithelial cells and kidney infiltrating T cells via ICOS-L and B7-H1 may change the balance of positive and negative signals to the T cells (PMID:16221208)
• dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes Sjogren syndrome (PMID:16265694)
• B7-H1 is inducible renal tubular epithelial antigen that inhibits T cell activation. B7-H1/PD-1 pathway might play role in protecting tubular epithelium from immune-mediated damage. B7-H1 may be therapeutic strategy in autoimmune renal diseases. (PMID:16282703)
• Our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominantly in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion. (PMID:16482562)
• B7-H1 is involved in suppression of T cell proliferation and IL-2 synthesis, roles suggested for B7-H1 on the gastric epithelium that contribute to the chronicity of Helicobacter pylori infection. (PMID:16493058)
• Multivariate analysis demonstrated that PD-L1 immunodetection could be used as an independent factor to evaluate the prognosis of gastric carcinoma. (PMID:16530813)
• a novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes may contribute to the unique immunological properties of the liver (PMID:16876901)
• Overexpression reduces accessory immune functions of endothelial cells. (PMID:16916652)
• data do not support an association between systemic lupus erythematosus and SNP’s within the genes of the PDCD1 ligands PD-L1 and PD-L2 (PMID:17136123)
• The aberrant expression of B7-H1 in urothelial cancer is associated with aggressive tumors, suggesting a regulatory role of tumor-associated B7-H1 in antitumor immunity. (PMID:17186290)
• Modulation of PD-L1 system may play a role in the development of autoimmune liver diseases. (PMID:17311651)
• Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. (PMID:17360651)
• Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma (PMID:17363736)
• Data show that sPD-Ll and its antibodies provide the basis for detection of the potential anti-PD-L1 antibodies and soluble PD-L1 in humans as well as for further investigation of its in vivo bioactivities and characterization of its potential receptors. (PMID:17366897)
• B7-H1 was downregulated in quiescent cells and upregulated in cells stimulated with a mitogen confirming the association of proliferation with the induction of B7-H1. (PMID:17415709)
• Elevated B7-H1 expression is closely associated with the suppression of T cell immune function in chronic hepatitis B patients. (PMID:17475895)
• Induction of cells of the T regulatory (Treg) phenotype by B7-H1 may play an important role in the T-cell suppression associated with Helicobacter pylori infection, as well as other infections that result in an up-regulation of B7-H1. (PMID:17562772)
• PD-L1 polymorphisms are not associated with susceptibility to rheumatoid arthritis, but 6777 G is associated with the prevalence of rheumatoid nodule in Taiwanese patients. (PMID:17597384)
• results indicate Hepatitis C virus core can upregulate a key negative T cell signaling pathway, PD-1/PDL-1, associated with viral persistence & expressed on T cells of infected individuals (PMID:17603844)
• chemopreventive agents were able to induce PD-L1 surface expression in human breast cancer cells, which then promoted PD-L1-mediated T cell apoptosis, a potential link between chemotherapy and cancer immunoresistance (PMID:17920123)
• PD-L1-deficient transgenic mice reconstituted with bone marrow from wild-type mice remain susceptible to severe myocarditis, demonstrating the protective effect of PD-L1 on non-bone marrow-derived cells. (PMID:17938288)
• results suggest that the PD-1/PD-L1 pathway may play a regulatory role in memory T cell subsets in addition to its association with T-cell exhaustion (PMID:17942371)
• B7-H1 and PD-1 expressions in patients with chronic hepatitis B are closely associated with their disease status. (PMID:17963598)
• There is no significant difference in B7-H1 expression on T cells and B cells between chronic hepatitis B patients and healthy subjects. (PMID:18024277)
• Blockade of the B7-H1 pathway may represent an attractive approach in the treatment of chronic hepatitis C. (PMID:18086898)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd274	ENSMUSG00000016496
rattus_norvegicus	Cd274	ENSRNOG00000016112

Paralogs (12): CD86 (ENSG00000114013), CD80 (ENSG00000121594), RFPL1 (ENSG00000128250), RFPL2 (ENSG00000128253), RFPL3 (ENSG00000128276), SPRYD4 (ENSG00000176422), RNF152 (ENSG00000176641), RNF135 (ENSG00000181481), PDCD1LG2 (ENSG00000197646), RFPL4A (ENSG00000223638), RFPL4AL1 (ENSG00000229292), RFPL4B (ENSG00000251258)

Protein

Protein identifiers

Programmed cell death 1 ligand 1 — Q9NZQ7 (reviewed: Q9NZQ7)

Alternative names: B7 homolog 1

All UniProt accessions (1): Q9NZQ7

UniProt curated annotations — full annotation on UniProt →

Function. Plays a critical role in induction and maintenance of immune tolerance to self. As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response. Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10). Can also act as a transcription coactivator: in response to hypoxia, translocates into the nucleus via its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis. The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival. The interaction with PDCD1/PD-1 inhibits cytotoxic T lymphocytes (CTLs) effector function. The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy.

Subunit / interactions. Interacts with PDCD1. Interacts (via transmembrane domain) with CMTM4 and CMTM6. Interacts with (phosphorylated) STAT3; promoting nuclear translocation. Interacts with CD80. May form homomultimers.

Subcellular location. Cell membrane. Early endosome membrane. Recycling endosome membrane. Nucleus Cell membrane Endomembrane system Secreted.

Tissue specificity. Highly expressed in the heart, skeletal muscle, placenta and lung. Weakly expressed in the thymus, spleen, kidney and liver. Expressed on activated T- and B-cells, dendritic cells, keratinocytes and monocytes. Widely expressed, highest in lung, liver and pituitary and in various peripheral blood cells, including neutrophils and some subtypes of lymphoid and myeloid cells.

Post-translational modifications. Ubiquitinated; STUB1 likely mediates polyubiquitination of PD-L1/CD274 triggering its degradation. Ubiquitinated by MARCHF8; leading to degradation. Deubiquitinated by USP22; leading to stabilization.

Disease relevance. Autoimmune disease, multisystem, infantile-onset, 5 (ADMIO5) [MIM:621235] An autosomal recessive disorder characterized by autoimmune manifestations apparent in the first months or years of life. ADMIO5 patients have complete insulin deficiency and type 1 diabetes mellitus with neonatal onset. The disease is caused by variants affecting the gene represented in this entry. Truncation of the 3’-untranslated (3’-UTR) region of CD274 transcripts leads to elevated expression of CD274 in multiple cancers including T-cell leukemia, diffuse large B-cell lymphoma and stomach adenocarcinoma. Disruption of 3’-UTR region is caused by structural variants that stabilize CD274 transcripts, leading to overexpression. Increased expression in tumors promotes immune evasion and tumor cell growth by allowing malignant cells to escape destruction by the immune system.

Induction. Up-regulated on T- and B-cells, dendritic cells, keratinocytes and monocytes after LPS and IFNG activation. Up-regulated in B-cells activated by surface Ig cross-linking.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the immunoglobulin superfamily. BTN/MOG family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NZQ7-1	1, PD-L1I	yes
Q9NZQ7-2	2, PD-L1II
Q9NZQ7-3	3
Q9NZQ7-4	4, secPD-L1

RefSeq proteins (2): NP_001254635, NP_054862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051713	T-cell_Activation_Regulation	Family

Pfam: PF07686, PF08205

UniProt features (45 total): strand 18, helix 6, glycosylation site 4, splice variant 4, turn 3, disulfide bond 2, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

76 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5O45	X-RAY DIFFRACTION	0.99
8ALX	X-RAY DIFFRACTION	1.1
6NP9	X-RAY DIFFRACTION	1.27
9I0U	X-RAY DIFFRACTION	1.46
6YCR	X-RAY DIFFRACTION	1.54
8AOK	X-RAY DIFFRACTION	1.6
7CZD	X-RAY DIFFRACTION	1.64
5JDS	X-RAY DIFFRACTION	1.7
5N2F	X-RAY DIFFRACTION	1.7
9QSM	X-RAY DIFFRACTION	1.75
8ZNL	X-RAY DIFFRACTION	1.77
5C3T	X-RAY DIFFRACTION	1.8
7OUN	X-RAY DIFFRACTION	1.9
6NNV	X-RAY DIFFRACTION	1.92
8XR5	X-RAY DIFFRACTION	1.95
4Z18	X-RAY DIFFRACTION	1.95
7C88	X-RAY DIFFRACTION	2
6PV9	X-RAY DIFFRACTION	2
7SJQ	X-RAY DIFFRACTION	2
5NIU	X-RAY DIFFRACTION	2.01
9IJT	X-RAY DIFFRACTION	2.05
9I0W	X-RAY DIFFRACTION	2.1
8P1O	X-RAY DIFFRACTION	2.17
5J89	X-RAY DIFFRACTION	2.2
6R3K	X-RAY DIFFRACTION	2.2
8K5N	X-RAY DIFFRACTION	2.2
8AOM	X-RAY DIFFRACTION	2.2
13FL	X-RAY DIFFRACTION	2.22
7UXO	X-RAY DIFFRACTION	2.25
3SBW	X-RAY DIFFRACTION	2.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZQ7-F1	88.13	0.70

Antibody-complex structures (SAbDab): 13 — 5GGT, 5GRJ, 5JDS, 5X8L, 5X8M, 5XJ4, 5XXY, 7C88, 7CZD, 7YDS, 8AOK, 8AOM, 8RPB

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 40–114, 155–209

Glycosylation sites (4): 219, 35, 192, 200

Mutagenesis-validated functional residues (1):

Position	Phenotype
238	largely abrogates multimerization, in vitro.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-389948	Co-inhibition by PD-1
R-HSA-9701898	STAT3 nuclear events downstream of ALK signaling
R-HSA-9909620	Regulation of PD-L1(CD274) translation
R-HSA-9929356	GSK3B-mediated proteasomal degradation of PD-L1(CD274)
R-HSA-9929491	SPOP-mediated proteasomal degradation of PD-L1(CD274)
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane
R-HSA-9909649	Regulation of PD-L1(CD274) transcription

MSigDB gene sets: 442 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE

GO Biological Process (23): adaptive immune response (GO:0002250), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), immune response (GO:0006955), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), T cell costimulation (GO:0031295), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-10 production (GO:0032693), positive regulation of interleukin-10 production (GO:0032733), response to cytokine (GO:0034097), TRIF-dependent toll-like receptor signaling pathway (GO:0035666), positive regulation of T cell proliferation (GO:0042102), negative regulation of T cell proliferation (GO:0042130), negative regulation of activated T cell proliferation (GO:0046007), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), cellular response to lipopolysaccharide (GO:0071222), negative regulation of tumor necrosis factor superfamily cytokine production (GO:1903556), positive regulation of activated CD8-positive, alpha-beta T cell apoptotic process (GO:1905404), negative regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000562), negative regulation of CD8-positive, alpha-beta T cell activation (GO:2001186), immune system process (GO:0002376), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (11): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), actin cytoskeleton (GO:0015629), early endosome membrane (GO:0031901), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), extracellular region (GO:0005576), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of PD-L1(CD274) Post-translational modification	4
Regulation of PD-L1(CD274) expression	2
Regulation of T cell activation by CD28 family	1
Signaling by ALK	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of cytokine production	3
signal transduction	2
positive regulation of T cell activation	2
interleukin-10 production	2
regulation of interleukin-10 production	2
T cell proliferation	2
regulation of T cell proliferation	2
plasma membrane	2
endosome membrane	2
immune response	1
T cell mediated immune response to tumor cell	1
negative regulation of T cell mediated immunity	1
negative regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lymphocyte costimulation	1
type II interferon production	1
regulation of type II interferon production	1
positive regulation of cytokine production	1
response to peptide	1
MyD88-independent toll-like receptor signaling pathway	1
positive regulation of lymphocyte proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
negative regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
T cell activation	1
regulation of T cell activation	1
negative regulation of lymphocyte activation	1

Protein interactions and networks

STRING

4400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD274	PDCD1	Q15116	999
CD274	CTLA4	P16410	999
CD274	HAVCR2	Q8TDQ0	998
CD274	CD28	P10747	997
CD274	ICOS	Q9Y6W8	995
CD274	CD80	P33681	989
CD274	LAG3	P18627	975
CD274	TIGIT	Q495A1	973
CD274	PDCD1LG2	Q9BQ51	970
CD274	CD86	P42081	969
CD274	STAT3	P40763	968
CD274	BTLA	Q7Z6A9	940
CD274	CD8A	P01732	937
CD274	FOXP3	Q9BZS1	912
CD274	MTUS1	Q9ULD2	909
CD274	MTUS2	Q5JR59	909

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CD80	CD274	psi-mi:“MI:0407”(direct interaction)	0.950
CD274	CD80	psi-mi:“MI:0407”(direct interaction)	0.950
CD80	CD274	psi-mi:“MI:0915”(physical association)	0.950
CD274	CD80	psi-mi:“MI:0915”(physical association)	0.950
CD274	PDCD1	psi-mi:“MI:0407”(direct interaction)	0.890
PDCD1	CD274	psi-mi:“MI:0407”(direct interaction)	0.890
CD274	PDCD1	psi-mi:“MI:0915”(physical association)	0.890
PDCD1	CD274	psi-mi:“MI:0915”(physical association)	0.890

BioGRID (551): SLC39A11 (Affinity Capture-MS), THADA (Affinity Capture-MS), XPO7 (Affinity Capture-MS), UTP20 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), XPO6 (Affinity Capture-MS), IPO7 (Affinity Capture-MS), ATR (Affinity Capture-MS), TMEM160 (Affinity Capture-MS), TNPO2 (Affinity Capture-MS), TNPO1 (Affinity Capture-MS), SAAL1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), HEATR1 (Affinity Capture-MS), COG2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E4BZH1, A7TZE6, A7TZF0, A7TZF3, A7TZG1, A7TZG3, A7XUX6, A7XV04, A7XV07, A7XV14, O54709, O70215, O95727, P0C1X9, P0DTI4, P26718, P42081, P61252, P83556, Q00609, Q29ZQ1, Q2YHT7, Q5RFR2, Q5UKY4, Q60651, Q60652, Q60654, Q60660, Q61885, Q63203, Q64329, Q68D85, Q6Q8B3, Q6XJV4, Q7Z6M3, Q8BG84, Q8BTP3, Q8MJH1, Q8TD46, Q921W8

Diamond homologs: A2AAJ9, A2ABU4, A8WQH2, B4QC63, O42127, P18461, P21803, P22455, P22607, P29294, P29317, P35969, P53767, P54755, Q03145, Q04589, Q1KL86, Q26474, Q2EY13, Q2EY14, Q2EY15, Q2VWP7, Q2VWP9, Q3UQ28, Q589G5, Q5STE3, Q5VTT5, Q61851, Q6AWJ9, Q6MZW2, Q7T2H2, Q868Z9, Q8BFR2, Q8BQC3, Q8IUL8, Q8IVU1, Q8N475, Q8TDY8, Q90Z00, Q91147

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
HIF1A	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
STAT3	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
KMT2C	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
FKBP5	“up-regulates quantity by expression”	CD274	“catalytic activity”
SIGMAR1	“up-regulates quantity by stabilization”	CD274	stabilization
STT3A	“up-regulates quantity by stabilization”	CD274	glycosylation
STT3B	“up-regulates quantity by stabilization”	CD274	glycosylation
COPS5	“up-regulates quantity by stabilization”	CD274	deubiquitination
SPOP	“down-regulates quantity”	CD274	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CD274	destabilization
CMTM6	“up-regulates quantity by stabilization”	CD274	stabilization
CMTM4	“up-regulates quantity by stabilization”	CD274	stabilization
B3GNT3	“up-regulates activity”	CD274	glycosylation
GSK3B	“down-regulates quantity by destabilization”	CD274	phosphorylation
SCF-betaTRCP	“down-regulates quantity by destabilization”	CD274	polyubiquitination
GSK3A	“down-regulates quantity by destabilization”	CD274	phosphorylation
ARIH1	“down-regulates quantity by destabilization”	CD274	polyubiquitination
FOXP3	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
ARIH1	“down-regulates quantity by destabilization”	CD274	ubiquitination
ITCH	“down-regulates quantity by destabilization”	CD274	ubiquitination
GSK3B	“down-regulates quantity”	CD274	phosphorylation
CD274	up-regulates	PDCD1	binding
NEK2	“up-regulates quantity by stabilization”	CD274	phosphorylation

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

CD274, also commonly referred to as PDL1, is a ligand that binds with the receptor PD1, commonly found on T-cells, and acts to block T-cell activation. PD1 expression has been observed in a variety of cancers including melanoma and non-small cell lung cancer. The interaction of PD1/PDL1 is hypothesized to be a possible mechanism for the tumor to escape immune response. A number of checkpoint blockade inhibitors including pembrolizumab and nivolumab have been developed that target the PD1/PDL1 interaction in order to allow T-cells to recognize tumor cells without being deactivated by the tumor.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — DLBCLNOS.

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	13
Likely benign	2
Benign	5

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1703576	GRCh37/hg19 9p24.3-q13(chr9:203861-68342786)	Pathogenic
1706515	GRCh37/hg19 9p24.3-23(chr9:203861-10283912)x1	Pathogenic
3906943	CD274, IVS4DS, G-A, +1	Pathogenic
442671	GRCh37/hg19 9p24.3-23(chr9:203861-13486759)x1	Pathogenic
4819211	Single allele	Pathogenic
563686	GRCh37/hg19 9p24.3-q21.11(chr9:203861-70985795)x4	Pathogenic

SpliceAI

1102 predictions. Top by Δscore:

Variant	Effect	Δscore
9:5450594:CAG:C	donor_loss	1.0000
9:5450595:AGG:A	donor_loss	1.0000
9:5462832:A:AG	acceptor_gain	1.0000
9:5462833:G:GA	acceptor_gain	1.0000
9:5450596:GG:G	donor_loss	0.9900
9:5450597:GTA:G	donor_loss	0.9900
9:5450598:T:G	donor_loss	0.9900
9:5457077:A:AG	acceptor_gain	0.9900
9:5457078:G:GG	acceptor_gain	0.9900
9:5457078:GC:G	acceptor_gain	0.9900
9:5457078:GCAT:G	acceptor_gain	0.9900
9:5457421:GT:G	donor_loss	0.9900
9:5457422:T:G	donor_loss	0.9900
9:5462826:T:G	acceptor_gain	0.9900
9:5462829:CCTA:C	acceptor_loss	0.9900
9:5462830:CTA:C	acceptor_loss	0.9900
9:5462831:TA:T	acceptor_loss	0.9900
9:5462832:A:AC	acceptor_loss	0.9900
9:5462833:GC:G	acceptor_gain	0.9900
9:5462833:GCC:G	acceptor_gain	0.9900
9:5462833:GCCC:G	acceptor_gain	0.9900
9:5462833:GCCCC:G	acceptor_gain	0.9900
9:5466827:GTG:G	donor_gain	0.9900
9:5456093:T:G	acceptor_gain	0.9800
9:5456096:TTA:T	acceptor_loss	0.9800
9:5456097:TAG:T	acceptor_loss	0.9800
9:5456098:A:C	acceptor_loss	0.9800
9:5456098:AG:A	acceptor_gain	0.9800
9:5456099:G:A	acceptor_loss	0.9800
9:5456099:GG:G	acceptor_gain	0.9800

AlphaMissense

1923 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:5462940:G:C	W167C	0.995
9:5462940:G:T	W167C	0.995
9:5457366:T:A	C114S	0.994
9:5457367:G:C	C114S	0.994
9:5462938:T:A	W167R	0.993
9:5462938:T:C	W167R	0.993
9:5457144:T:A	C40S	0.991
9:5457145:G:C	C40S	0.991
9:5457197:G:C	W57C	0.991
9:5457197:G:T	W57C	0.991
9:5457360:T:G	Y112D	0.990
9:5457366:T:C	C114R	0.990
9:5462902:T:A	C155S	0.987
9:5462903:G:C	C155S	0.987
9:5457144:T:C	C40R	0.986
9:5457368:C:G	C114W	0.986
9:5462902:T:C	C155R	0.986
9:5463064:T:A	C209S	0.986
9:5463065:G:C	C209S	0.986
9:5457151:T:G	F42C	0.985
9:5457150:T:C	F42L	0.984
9:5457152:C:A	F42L	0.984
9:5457152:C:G	F42L	0.984
9:5457367:G:A	C114Y	0.984
9:5457349:A:C	D108A	0.983
9:5457322:T:C	L99P	0.982
9:5462897:T:C	L153P	0.982
9:5462908:G:C	A157P	0.982
9:5457349:A:T	D108V	0.979
9:5457322:T:A	L99H	0.978

dbSNP variants (sampled 300 via entrez): RS1000236972 (9:5469948 C>T), RS1000430255 (9:5451976 G>A), RS1000608610 (9:5448692 A>G), RS1000659170 (9:5449701 A>G), RS1000736188 (9:5454955 G>C), RS1000804828 (9:5460920 A>G), RS1001314041 (9:5468067 G>A,C,T), RS1001330894 (9:5470634 C>T), RS1001444041 (9:5451053 A>G), RS1001457252 (9:5465356 C>T), RS1001549225 (9:5468406 C>A,T), RS1001812812 (9:5467143 C>T), RS1002078655 (9:5450434 A>G), RS1002089984 (9:5450017 A>C), RS1002143080 (9:5455611 G>C)

Disease associations

OMIM: gene MIM:605402 | disease phenotypes: MIM:621235

GenCC curated gene-disease

Disease	Classification	Inheritance
neonatal diabetes mellitus	Limited	Autosomal recessive

Mondo (3): autoimmune disease, multisystem, infantile-onset, 5 (MONDO:0979235), trisomy 9p (MONDO:0016526), neonatal diabetes mellitus (MONDO:0016391)

Orphanet (2): Trisomy 9p syndrome (Orphanet:236), Partial duplication/triplication of the short arm of chromosome 9 syndrome (Orphanet:262767)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0002099	Asthma
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0011950	Bronchiolitis
HP:0025329	Anti-glutamic acid decarboxylase antibody positivity
HP:0025373	Interictal EEG abnormality
HP:0025379	Anti-thyroid peroxidase antibody positivity
HP:0030795	Reduced C-peptide level
HP:0034063	Anti-islet antigen-2 antibody positivity
HP:0034323	Reduced circulating growth hormone concentration
HP:0100651	Type I diabetes mellitus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_2440	Blood protein levels	2.000000e-29

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL3580522 (SINGLE PROTEIN), CHEMBL4523993 (PROTEIN COMPLEX), CHEMBL5739543 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066575 (PROTEIN FAMILY), CHEMBL6195520 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 43,843 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL86304	MOCLOBEMIDE	4	13,492
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL444633	RIFABUTIN	4	27,819
CHEMBL5095237	EVIXAPODLIN	1	735

Clinical evidence (CIViC)

Drug × variant × indication: 12 predictive associations from 15 curated evidence items; also 10 prognostic, 1 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
CD274 Expression	Atezolizumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1172 +1
CD274 Expression	Pembrolizumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1733 +1
CD274 Expression	Nivolumab + Pembrolizumab	Melanoma	Sensitivity/Response	CIViC B	EID704 +1
CD274 Expression	Atezolizumab + Avelumab + Nivolumab + Pembrolizumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1167
CD274 Expression	Nivolumab	Cancer	Sensitivity/Response	CIViC B	EID1517
CD274 Expression	Pembrolizumab	Merkel Cell Carcinoma	Sensitivity/Response	CIViC B	EID1578
CD274 Expression	Ipilimumab + Nivolumab	Melanoma	Sensitivity/Response	CIViC B	EID1615
CD274 Expression	Atezolizumab + Avelumab + Pembrolizumab + Nivolumab + Durvalumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID4857
CD274 Expression	Pembrolizumab + Nivolumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID743
CD274 Expression	Nivolumab	Nasopharynx Carcinoma	Sensitivity/Response	CIViC B	EID9010
CD274 Expression	Atezolizumab	Bladder Urothelial Carcinoma	Sensitivity/Response	CIViC B	EID9886
CD274 Expression	Radiation Therapy	Head And Neck Squamous Cell Carcinoma	Resistance	CIViC B	EID3000

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2297136	CD274		0.00	0
rs822336	CD274		0.00	0
rs2282055	CD274		0.00	0

Binding affinities (BindingDB)

958 measured of 1279 human assays (1279 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.064 nM	US-10710986: PD-1/PD-L1 inhibitors
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[2-(2H-triazol-4-yl)ethylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.138 nM	US-10710986: PD-1/PD-L1 inhibitors
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[2-(1H-1,2,4-triazol-5-yl)ethylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.159 nM	US-10710986: PD-1/PD-L1 inhibitors
3-[[[6-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-2-methoxy-3-pyridinyl]methylamino]methyl]-1,2,4-oxadiazolidin-5-one	IC50	0.167 nM	US-10710986: PD-1/PD-L1 inhibitors
US12473282, Example 75	IC50	0.185 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
US12473282, Example 73	IC50	0.186 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[(2H-triazol-4-ylmethylamino)methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.191 nM	US-10710986: PD-1/PD-L1 inhibitors
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[(2-hydroxyethylamino)methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.191 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[4-methoxy-5-(pyrrolidin-1-ylmethyl)-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.193 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[3-[3-[(Z)-2-[5-[[[(1R)-1-carboxy-2-hydroxyethyl]amino]methyl]-4-methoxy-2-pyridinyl]-2-fluoroethenyl]-2-chlorophenyl]-2-chlorophenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.202 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[(3-hydroxy-3-methylpyrrolidin-1-yl)methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.232 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.238 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[4-methoxy-5-[(propan-2-ylamino)methyl]-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.249 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5R)-5-[[[5-[2-chloro-3-[2-chloro-3-[5-[[2-(1H-imidazol-2-yl)ethylamino]methyl]-6-methoxypyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.28 nM	US-10710986: PD-1/PD-L1 inhibitors
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.299 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-[4-cyclopropyl-5-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-2-pyridinyl]-2-fluoroethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.306 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[[(4-hydroxycyclohexyl)amino]methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.31 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[[2-[[3-[3-[(Z)-2-fluoro-2-[4-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]-2-pyridinyl]ethenyl]-2-methylphenyl]-2-methylphenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]methyl]cyclohexane-1-carboxylic acid	IC50	0.331 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-[5-[(2,2-difluoroethylamino)methyl]-4-methoxy-2-pyridinyl]-2-fluoroethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.332 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[3-(1H-pyrazol-5-yl)pyrrolidin-1-yl]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.342 nM	US-10710986: PD-1/PD-L1 inhibitors
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[3-(1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.346 nM	US-10710986: PD-1/PD-L1 inhibitors
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[4-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.352 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[2-(1H-pyrazol-4-yl)ethylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.356 nM	US-10710986: PD-1/PD-L1 inhibitors
(2R)-2-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-(2-piperidin-1-ylethoxy)phenyl]methylamino]-3-hydroxy-2-methylpropanoic acid	IC50	0.4 nM	US-20250230153
1-[2-[2-[[[(2R)-2-carboxy-1-hydroxypropan-2-yl]amino]methyl]-4-chloro-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]phenoxy]ethyl]-4-hydroxypiperidine-4-carboxylic acid	IC50	0.4 nM	US-20250230153
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[(2R)-2-hydroxypropyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-2-yl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.419 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[(1H-1,2,4-triazol-5-ylmethylamino)methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.436 nM	US-10710986: PD-1/PD-L1 inhibitors
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[(4,5,6,7-tetrahydro-1H-indazol-6-ylamino)methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.48 nM	US-10710986: PD-1/PD-L1 inhibitors
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.489 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
2-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[2-[(3R)-3-hydroxypyrrolidin-1-yl]ethoxy]phenyl]methylamino]-2-methylpropane-1,3-diol	IC50	0.5 nM	US-20250230153
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-(1-methyl-5-propan-2-yl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-2-yl)ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.516 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[3-[3-[5-[[3-(1H-benzimidazol-2-yl)propylamino]methyl]-6-methoxypyrazin-2-yl]-2-chlorophenyl]-2-chlorophenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.542 nM	US-10710986: PD-1/PD-L1 inhibitors
(2S)-1-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-(2-piperidin-1-ylethoxy)phenyl]methyl]piperidine-2-carboxylic acid	IC50	0.6 nM	US-20250230153
1-[2-[4-chloro-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[[(1,3-dihydroxy-2-methylpropan-2-yl)amino]methyl]phenoxy]ethyl]-4-hydroxypiperidine-4-carboxylic acid	IC50	0.6 nM	US-20250230153
4-[2-[2-[[2-chloro-3-[2-chloro-3-[(Z)-2-fluoro-2-[5-[[[(3S,4R)-3-hydroxyoxan-4-yl]amino]methyl]-4-methoxy-2-pyridinyl]ethenyl]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.638 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[5-[[[2-hydroxy-1-(2H-tetrazol-5-yl)ethyl]amino]methyl]-6-methoxypyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.66 nM	US-10710986: PD-1/PD-L1 inhibitors
4-[2-[2-[[3-[3-[(Z)-2-fluoro-2-(1-methyl-5-propan-2-yl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-2-yl)ethenyl]-2-methylphenyl]-2-methylphenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.688 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
4-[2-[2-[[3-[3-[(Z)-2-[5-[(tert-butylamino)methyl]-4-methoxy-2-pyridinyl]-2-fluoroethenyl]-2-chlorophenyl]-2-chlorophenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	0.731 nM	US-12473282: Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[5-[[ethyl-[2-(1H-pyrazol-4-yl)ethyl]amino]methyl]-6-methoxypyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	0.822 nM	US-10710986: PD-1/PD-L1 inhibitors
N-(2-(4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-2-((5-cyanopyridin-3-yl)methoxy)-5-methylbenzylamino)ethyl)acetamide	IC50	0.92 nM	US-9850225: Compounds useful as immunomodulators
(2S)-1-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[2-(4-hydroxy-4-methoxycarbonylpiperidin-1-yl)ethoxy]phenyl]methyl]piperidine-2-carboxylic acid	IC50	1 nM	US-20250230153
(2S)-2-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[[5-(3-methoxy-3-oxopropyl)sulfanyl-3-pyridinyl]methoxy]phenyl]methylamino]-3-hydroxy-2-methylpropanoic acid	IC50	1.1 nM	US-20250230153
US20250340529, Compound 388	IC50	1.1 nM	US-20250340529: Heterocyclic Compounds as Immunomodulators of PD-L1 Interactions
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-hydroxybutanoic acid	IC50	1.19 nM	US-9850225: Compounds useful as immunomodulators
(2R)-2-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-(4,4,4-trifluorobutoxy)phenyl]methylamino]-3-hydroxy-2-methylpropanoic acid	IC50	1.2 nM	US-20250230153
(2R)-2-[[5-chloro-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[2-(4-hydroxy-4-methoxycarbonylpiperidin-1-yl)ethoxy]phenyl]methylamino]-3-hydroxy-2-methylpropanoic acid	IC50	1.3 nM	US-20250230153
(2R,4R)-1-[[5-chloro-2-[(3-cyanophenyl)methoxy]-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]phenyl]methyl]-4-hydroxypyrrolidine-2-carboxylic acid	IC50	1.4 nM	US-9850225: Compounds useful as immunomodulators
methyl 1-[2-[4-chloro-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]-2-[[(1,3-dihydroxy-2-methylpropan-2-yl)amino]methyl]phenoxy]ethyl]-4-hydroxypiperidine-4-carboxylate	IC50	1.4 nM	US-20250230153
(2S,4R)-1-[2-[7-[3-[3-[4-[2-[(2S,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl]ethyl]-3-oxo-1,4-benzoxazin-7-yl]-2-chlorophenyl]-2-chlorophenyl]-3-oxo-1,4-benzoxazin-4-yl]ethyl]-4-hydroxypyrrolidine-2-carboxylic acid	IC50	1.42 nM	US-20250340529: Heterocyclic Compounds as Immunomodulators of PD-L1 Interactions
4-[[[6-[[3-[3-[[5-[[(4-carboxy-1-bicyclo[2.2.1]heptanyl)methylamino]methyl]-4-cyclopropylpyridine-2-carbonyl]amino]-2-methylphenyl]-2-methylphenyl]carbamoyl]-4-cyclopropyl-3-pyridinyl]methylamino]methyl]bicyclo[2.2.1]heptane-1-carboxylic acid	IC50	1.46 nM	US-20250179023: HOLOSYMMETRIC BIPHENYL DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

ChEMBL bioactivities

5925 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL5411833
10.72	Kd	0.019	nM	CHEMBL4473436
10.49	IC50	0.032	nM	CHEMBL6041367
10.47	IC50	0.034	nM	CHEMBL5816891
10.40	IC50	0.04	nM	CHEMBL5182195
10.40	IC50	0.04	nM	CHEMBL6061706
10.29	IC50	0.051	nM	CHEMBL4865838
10.24	IC50	0.058	nM	CHEMBL4862360
10.22	IC50	0.06	nM	CHEMBL5890938
10.22	IC50	0.06	nM	CHEMBL5777528
10.22	IC50	0.06	nM	CHEMBL5889053
10.22	IC50	0.06	nM	CHEMBL5743690
10.22	IC50	0.06	nM	CHEMBL5920904
10.22	IC50	0.06	nM	CHEMBL5831012
10.19	IC50	0.064	nM	CHEMBL6025911
10.19	IC50	0.064	nM	CHEMBL5944322
10.19	IC50	0.064	nM	CHEMBL5975129
10.19	IC50	0.064	nM	CHEMBL5971416
10.19	IC50	0.064	nM	CHEMBL5926015
10.19	IC50	0.064	nM	CHEMBL5917876
10.19	IC50	0.064	nM	CHEMBL5970033
10.19	IC50	0.064	nM	CHEMBL5755581
10.19	IC50	0.064	nM	CHEMBL5965337
10.19	IC50	0.064	nM	CHEMBL6020002
10.19	IC50	0.064	nM	CHEMBL5773471
10.19	IC50	0.064	nM	CHEMBL6053156
10.19	IC50	0.064	nM	CHEMBL5791950
10.19	IC50	0.064	nM	CHEMBL5833807
10.19	IC50	0.064	nM	CHEMBL5826045
10.19	IC50	0.064	nM	CHEMBL5785770
10.19	IC50	0.064	nM	CHEMBL5964067
10.19	IC50	0.064	nM	CHEMBL6006236
10.19	IC50	0.064	nM	CHEMBL5785148
10.19	IC50	0.064	nM	CHEMBL5826709
10.19	IC50	0.064	nM	CHEMBL5758891
10.19	IC50	0.064	nM	CHEMBL5948806
10.19	IC50	0.064	nM	CHEMBL5856770
10.19	IC50	0.064	nM	CHEMBL5989882
10.19	IC50	0.064	nM	CHEMBL5827762
10.19	IC50	0.064	nM	CHEMBL6037230
10.19	IC50	0.064	nM	CHEMBL5966006
10.19	IC50	0.064	nM	CHEMBL5864311
10.19	IC50	0.064	nM	CHEMBL5894438
10.19	IC50	0.064	nM	CHEMBL5971082
10.19	IC50	0.064	nM	CHEMBL5772234
10.19	IC50	0.064	nM	CHEMBL5847490
10.19	IC50	0.064	nM	CHEMBL6008168
10.19	IC50	0.064	nM	CHEMBL5891751
10.19	IC50	0.064	nM	CHEMBL5765331
10.19	IC50	0.064	nM	CHEMBL5915120

PubChem BioAssay actives

1444 with measured affinity, of 2748 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-1-[[4-[[2-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]methoxy]-5-chloro-2-[(2-cyano-4-pyridinyl)methoxy]phenyl]methyl]piperidine-2-carboxylic acid	1985059: Inhibition of His-tagged PD-1 (unknown origin)/hFc-tagged PD-L1 (unknown origin) protein-protein interaction incubated for 15 mins by HTRF assay	ic50	<0.0001	uM
(2S)-1-[[4-[(2-bromo-3-phenylphenyl)methoxy]-5-chloro-2-[(2-cyano-4-pyridinyl)methoxy]phenyl]methyl]piperidine-2-carboxylic acid	1985059: Inhibition of His-tagged PD-1 (unknown origin)/hFc-tagged PD-L1 (unknown origin) protein-protein interaction incubated for 15 mins by HTRF assay	ic50	<0.0001	uM
(2S)-1-[[4-[(2-bromo-3-phenylphenyl)methoxy]-5-chloro-2-[(5-cyano-3-pyridinyl)methoxy]phenyl]methyl]piperidine-2-carboxylic acid	1985059: Inhibition of His-tagged PD-1 (unknown origin)/hFc-tagged PD-L1 (unknown origin) protein-protein interaction incubated for 15 mins by HTRF assay	ic50	<0.0001	uM
(2R)-2-[[4-[[3-[3-[[4-[[[(1R)-1-carboxy-2-hydroxyethyl]amino]methyl]-3-[(5-cyano-3-pyridinyl)methoxy]phenoxy]methyl]-2-methylphenyl]-2-methylphenyl]methoxy]-2-[(5-cyano-3-pyridinyl)methoxy]phenyl]methylamino]-3-hydroxypropanoic acid	1634345: Binding affinity to FC-tagged human PDL1 by SPR assay	kd	<0.0001	uM
(2S)-1-[[4-[2-(2-bromo-3-phenylphenyl)ethyl]-5-chloro-2-[(2-cyano-4-pyridinyl)methoxy]phenyl]methyl]piperidine-2-carboxylic acid	1533369: Inhibition of recombinant human PD1 (25 to 167 residues)/human PDL1 (19 to 238 residues) interaction after 40 mins by HTRF assay	ic50	<0.0001	uM
(2S)-2-[[4-[[3-[3-[[4-[[[(1R)-1-carboxy-3-hydroxypropyl]amino]methyl]-2-chloro-5-[(3-cyanophenyl)methoxy]phenoxy]methyl]-2-methylphenyl]phenyl]methoxy]-5-chloro-2-(pyridin-3-ylmethoxy)phenyl]methylamino]-4-hydroxybutanoic acid	1845762: Inhibition of PD-1/PD-L1 interaction (unknown origin) by HTRF binding assay	ic50	<0.0001	uM
(2S)-1-[[4-[2-(2-bromo-3-phenylphenyl)ethyl]-2-[(2-cyano-4-pyridinyl)methoxy]phenyl]methyl]piperidine-2-carboxylic acid	1845764: Inhibition of His-tagged PD-1/PD-L1 interaction (unknown origin) incubated for 1 to 4 hrs by HTRF binding assay	ic50	<0.0001	uM
(2S,4S)-1-[[6-[[(1S)-4-[(1S)-1-[[5-[[(2S,4S)-2-carboxy-4-hydroxypyrrolidin-1-yl]methyl]-3-chloro-6-[(5-methylsulfonyl-3-pyridinyl)methoxy]-2-pyridinyl]oxy]-2,3-dihydro-1H-inden-4-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-5-chloro-2-[(5-methylsulfonyl-3-pyridinyl)methoxy]-3-pyridinyl]methyl]-4-hydroxypyrrolidine-2-carboxylic acid	1752584: Inhibition of PD1/PD-L1 (unknown origin)	ic50	0.0001	uM
(2S)-2-[[6-[[(1S)-4-[(1S)-1-[[5-[[[(2S)-2-carboxy-1-hydroxypropan-2-yl]amino]methyl]-3-chloro-6-[(5-methylsulfonyl-3-pyridinyl)methoxy]-2-pyridinyl]oxy]-2,3-dihydro-1H-inden-4-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-5-chloro-2-[(5-methylsulfonyl-3-pyridinyl)methoxy]-3-pyridinyl]methylamino]-3-hydroxy-2-methylpropanoic acid	1752584: Inhibition of PD1/PD-L1 (unknown origin)	ic50	0.0001	uM
(2R)-1-[[6-[[3-[3-[(2R)-2-amino-2,3-dihydro-1H-inden-5-yl]-2-chlorophenyl]-2-chlorophenyl]methoxy]-5-bromo-2-[2-(5-methylsulfonyl-3-pyridinyl)ethyl]-3-pyridinyl]methyl]piperidine-2-carboxylic acid	2035804: Inhibition of human PD-L1/PD-L1 interaction incubated for 15 mins by TR-FRET assay	ic50	0.0001	uM
(2S)-1-[[5-chloro-2-[(3-cyanophenyl)methoxy]-4-[[2-methyl-3-[2-methyl-3-(3-morpholin-4-ylpropoxy)phenyl]phenyl]methoxy]phenyl]methyl]piperidine-2-carboxylic acid	2035797: Inhibition of PD-L1 (unknown origin) by HTRF assay	ic50	0.0002	uM
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	2089806: Inhibition of PD-1/PD-L1 interaction (unknown origin)	ic50	0.0002	uM
(2R)-2-[[4-[[3-[3-[[4-[[[(1R)-1-carboxy-2-hydroxyethyl]amino]methyl]-3-[(5-cyano-3-pyridinyl)methoxy]phenoxy]methyl]-2-methylphenyl]phenyl]methoxy]-2-[(5-cyano-3-pyridinyl)methoxy]phenyl]methylamino]-3-hydroxypropanoic acid	1634345: Binding affinity to FC-tagged human PDL1 by SPR assay	kd	0.0002	uM
(2R)-2-[[4-[[3-[3-[[4-[[[(1R)-1-carboxy-2-hydroxyethyl]amino]methyl]-3-[(5-cyano-3-pyridinyl)methoxy]phenoxy]methyl]-2-methylphenyl]-2-methylphenyl]methoxy]-2-methoxyphenyl]methylamino]-3-hydroxypropanoic acid	1634345: Binding affinity to FC-tagged human PDL1 by SPR assay	kd	0.0002	uM
(5S)-5-[[[6-[2-chloro-3-[1-[4-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-3,5-dimethoxyphenyl]indazol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methylamino]methyl]pyrrolidin-2-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0002	uM
(5S)-5-[[[6-[2-chloro-3-[1-[3,5-dimethoxy-4-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenyl]indol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methylamino]methyl]pyrrolidin-2-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0002	uM
ethyl (E)-2-cyano-3-(3-cyanophenyl)prop-2-enoate	1985066: Inhibition of [89Zr]Zr-atezolizumab binding from human PD-L1 transfected in CHO cells preincubated for 30 mins followed by [89Zr]Zr-atezolizumab addition measured after 60 mins by Wizard2 gamma counter analysis	ki	0.0002	uM
2-[3-[[(3S,6S,9S,15S,18S,21S,27R,30S,33S,36S,39S,42S,45S,48S,50R)-42-(2-aminoethyl)-6-(aminomethyl)-15-(2-amino-2-oxoethyl)-27-[(2-amino-2-oxoethyl)carbamoyl]-33,36-dibutyl-50-hydroxy-21-[(4-hydroxyphenyl)methyl]-45-(1H-indol-3-ylmethyl)-18,19,34,37-tetramethyl-3,30-bis(2-methylpropyl)-2,5,8,14,17,20,23,29,32,35,38,41,44,47-tetradecaoxo-25-thia-1,4,7,13,16,19,22,28,31,34,37,40,43,46-tetradecazatricyclo[46.3.0.09,13]henpentacontan-39-yl]methyl]indol-1-yl]acetic acid	2099894: Inhibition of PD-1/PD-L1 (unknown origin) protein-protein interaction expressed in HEK293 cells by HTRF method	ic50	0.0003	uM
(2R)-2-[[4-[[3-[3-[[4-[[[(1R)-1-carboxy-2-hydroxyethyl]amino]methyl]-3-[(5-cyano-3-pyridinyl)methoxy]phenoxy]methyl]-2-methylphenyl]-2-methylphenyl]methoxy]phenyl]methylamino]-3-hydroxypropanoic acid	1634345: Binding affinity to FC-tagged human PDL1 by SPR assay	kd	0.0003	uM
2-[[6-[2-chloro-3-[1-[3,5-dimethoxy-4-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenyl]indazol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methyl]-2,5-diazaspiro[3.4]octan-6-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0003	uM
2-[[6-[2-chloro-3-[1-[3,5-dimethoxy-4-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenyl]indazol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methyl]-2,7-diazaspiro[3.4]octan-6-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0003	uM
2-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-3-[(2-amino-2-oxoethyl)carbamoyl]-9,36-dibenzyl-24,30-bis[(2S)-butan-2-yl]-6,15,21-tris[3-(diaminomethylideneamino)propyl]-33-(2-methylpropyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-12,27-di(propan-2-yl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-18-yl]acetic acid	1930232: Inhibition of human PD-1 expressed in rat PBMCs/human PD-L1 expressed in MDA-MB-231 cells protein-protein interaction assessed as increase in PBMCs proliferation	ec50	0.0004	uM
5-[(2-hydroxyethylamino)methyl]-N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methylphenyl]-2-methylphenyl]pyridine-2-carboxamide	1998919: Inhibition of PD-1 (unknown origin)/PD-L1 (unknown origin) interaction by HTRF binding assay	ic50	0.0004	uM
2-[[4-[4-[2-chloro-3-[5-[[(3-hydroxycyclobutyl)amino]methyl]-6-methoxy-2-pyridinyl]phenyl]indazol-1-yl]-2,6-dimethoxyphenyl]methyl]-2,7-diazaspiro[3.4]octan-6-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0004	uM
(5S)-5-[[[6-[2-chloro-3-[1-[4-[[(3-hydroxycyclobutyl)methylamino]methyl]-3,5-dimethoxyphenyl]indazol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methylamino]methyl]pyrrolidin-2-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0004	uM
(5S)-5-[[[4-[4-[3-[5-[(2-acetyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-6-methoxy-2-pyridinyl]-2-chlorophenyl]indazol-1-yl]-2,6-dimethoxyphenyl]methylamino]methyl]pyrrolidin-2-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0004	uM
5-[[4-chloro-5-[[3-[3-[3-(3,3-difluoropyrrolidin-1-yl)propoxy]-2-methylphenyl]-2-methylphenyl]methoxy]-2-[[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]-methylamino]methyl]phenoxy]methyl]pyridine-3-carbonitrile	1652976: Inhibition of human PD1/PDL1 protein-protein interaction by HTRF assay	ic50	0.0005	uM
(2S)-1-[[5-chloro-2-[(5-cyano-3-pyridinyl)methoxy]-4-[[3-[3-[3-(4-hydroxypiperidin-1-yl)propoxy]-2-methylphenyl]-2-methylphenyl]methoxy]phenyl]methyl]piperidine-2-carboxylic acid	2035797: Inhibition of PD-L1 (unknown origin) by HTRF assay	ic50	0.0005	uM
(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridinyl)methoxy]-4-[[3-[3-[3-(4-hydroxypiperidin-1-yl)propoxy]phenyl]-2-methylphenyl]methoxy]phenyl]methylamino]-3-hydroxypropanoic acid	1845762: Inhibition of PD-1/PD-L1 interaction (unknown origin) by HTRF binding assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N’,N’-dimethylpiperidine-4-carbohydrazide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]pyrrolidine-2-carboxylic acid	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(1,3-dihydroxypropan-2-yl)pyrrolidine-3-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
N-(2-aminoethyl)-1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]piperidine-4-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N’,N’-dimethylpyrrolidine-2-carbohydrazide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]piperidine-3-carboxylic acid	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(1,3-dihydroxypropan-2-yl)piperidine-4-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(1,3-dihydroxypropan-2-yl)pyrrolidine-2-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
N-(2-aminoethyl)-1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]pyrrolidine-2-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]pyrrolidine-2-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]pyrrolidine-3-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]piperidine-4-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]pyrrolidine-3-carbohydrazide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(2-hydroxyethyl)piperidine-3-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]piperidine-4-carboxylic acid	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0005	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(2-hydroxyethyl)piperidine-4-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0006	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]piperidine-2-carboxylic acid	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0006	uM
5-(3,4-dimethoxyphenyl)-2-pyridin-2-yl-4H-pyrazol-3-one	1908515: Binding affinity towards His-tagged recombinant human PD-L1 measured by MST dimerization binding assay	kd	0.0007	uM
(5S)-5-[[[6-[2-chloro-3-[1-[3,5-dimethoxy-4-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenyl]indazol-4-yl]phenyl]-2-methoxy-3-pyridinyl]methylamino]methyl]pyrrolidin-2-one	2128947: Inhibition of Fc-tagged recombinant human PD-1/His-tagged recombinant human PD-L1 interaction by ALPHA assay	ic50	0.0007	uM

CTD chemical–gene interactions

125 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	4
Lipopolysaccharides	increases expression, increases reaction, affects response to substance, affects cotreatment	3
Nickel	increases expression	3
immune checkpoint inhibitor BMS-1	affects binding, affects cotreatment, decreases expression, increases reaction	2
cinnamaldehyde	increases expression	2
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	2
nickel sulfate	decreases expression, increases expression	2
evodiamine	decreases expression, decreases reaction, increases expression	2
CPG-oligonucleotide	increases reaction, decreases reaction, increases expression	2
Benzo(a)pyrene	increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Cisplatin	decreases expression, increases reaction	2
Dinitrochlorobenzene	increases expression	2
Manganese	increases expression, decreases expression, increases abundance	2
Carboplatin	decreases expression	2
Lactic Acid	decreases reaction, increases expression, affects reaction	2
Particulate Matter	increases abundance, increases expression	2
Paris saponin VII	affects cotreatment, decreases expression, decreases phosphorylation	1
Glupearl 19S	increases expression	1
GW 506033X	increases expression	1
nano-diamino-tetrac	decreases expression, increases reaction, decreases reaction, increases expression	1
abivertinib	affects binding	1
sotorasib	affects cotreatment, decreases expression	1
disitamab vedotin	affects reaction, increases response to substance	1
TL8-506	affects cotreatment, increases expression	1
spinacetin	affects binding	1
kaempferol	affects binding	1
bisphenol A	decreases expression	1
kojic acid	increases expression	1
trichostatin A	increases expression	1

ChEMBL screening assays

525 unique, capped per target: 520 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3583018	Binding	Binding affinity to His-tagged PD-L1 (unknown origin) assessed as inhibition of interaction with PD1 preincubated for 15 mins followed by PD1 addition measured after 15 mins by HTRF assay	Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections. — ACS Med Chem Lett
CHEMBL4769870	Functional	Protac like activity at CRBN/PD-L1 in human MDA-MB-231 cells assessed as reduction in cell surface PD-L1 expression at 10 uM measured after 24 hrs by flow cytometry relative to control	Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1. — Eur J Med Chem

Cellosaurus cell lines

31 cell lines: 21 cancer cell line, 5 spontaneously immortalized cell line, 4 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8AE	Raji-hPD-L1	Cancer cell line	Male
CVCL_B1ER	Abcam A-549 CD274 KO 1	Cancer cell line	Male
CVCL_B2MA	Abcam A-549 CD274 KO 2	Cancer cell line	Male
CVCL_B7NL	MC38-hPD-L1	Cancer cell line	Female
CVCL_B7NP	CT26-hPD-L1	Cancer cell line	Female
CVCL_B7Q0	MC38-hPD-L1-LZ	Cancer cell line	Female
CVCL_C9D8	KSCBi005-A-8	Induced pluripotent stem cell	Male
CVCL_D2S5	LN229/hPD-L1	Cancer cell line	Female
CVCL_D2S6	CHO/hPD-L1	Spontaneously immortalized cell line	Female
CVCL_D6CP	HyCyte THP-1 KO-hCD274	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.