PDCD1

Summary

PDCD1 (programmed cell death 1, HGNC:8760) is a protein-coding gene on chromosome 2q37.3, encoding Programmed cell death protein 1 (Q15116). Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self.

Programmed cell death protein 1 (PDCD1) is an immune-inhibitory receptor expressed in activated T cells; it is involved in the regulation of T-cell functions, including those of effector CD8+ T cells. In addition, this protein can also promote the differentiation of CD4+ T cells into T regulatory cells. PDCD1 is expressed in many types of tumors including melanomas, and has demonstrated to play a role in anti-tumor immunity. Moreover, this protein has been shown to be involved in safeguarding against autoimmunity, however, it can also contribute to the inhibition of effective anti-tumor and anti-microbial immunity.

Source: NCBI Gene 5133 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 48 total — 1 pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005018

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8760
Approved symbol	PDCD1
Name	programmed cell death 1
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	CD279, PD1, hSLE1, PD-1
Ensembl gene	ENSG00000188389
Ensembl biotype	protein_coding
OMIM	600244
Entrez	5133

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 nonsense_mediated_decay

ENST00000334409, ENST00000343705, ENST00000418831, ENST00000718473, ENST00000718474, ENST00000890793, ENST00000944235

RefSeq mRNA: 1 — MANE Select: NM_005018 NM_005018

CCDS: CCDS33428

Canonical transcript exons

ENST00000334409 — 5 exons

Exon	Start	End
ENSE00001372954	241858763	241858894
ENSE00001384908	241852621	241852980
ENSE00003549266	241851949	241851983
ENSE00003605706	241852198	241852353
ENSE00004035194	241849884	241851297

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 85.78.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0771 / max 103.1572, expressed in 263 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34952	1.0502	260
34951	0.0270	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	85.78	gold quality
granulocyte	CL:0000094	78.92	gold quality
spleen	UBERON:0002106	75.99	gold quality
right atrium auricular region	UBERON:0006631	74.95	gold quality
vermiform appendix	UBERON:0001154	74.67	gold quality
blood	UBERON:0000178	74.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	66.51	gold quality
heart	UBERON:0000948	65.48	gold quality
small intestine	UBERON:0002108	65.43	gold quality
heart left ventricle	UBERON:0002084	65.13	gold quality
mucosa of transverse colon	UBERON:0004991	65.01	gold quality
upper lobe of left lung	UBERON:0008952	64.62	gold quality
tonsil	UBERON:0002372	63.71	gold quality
bone marrow	UBERON:0002371	63.35	gold quality
omental fat pad	UBERON:0010414	62.81	gold quality
fundus of stomach	UBERON:0001160	61.50	gold quality
body of stomach	UBERON:0001161	61.39	gold quality
gall bladder	UBERON:0002110	60.40	gold quality
adipose tissue	UBERON:0001013	60.20	gold quality
endocervix	UBERON:0000458	60.11	gold quality
pituitary gland	UBERON:0000007	59.68	gold quality
left uterine tube	UBERON:0001303	59.15	gold quality
stomach	UBERON:0000945	58.58	gold quality
lung	UBERON:0002048	58.49	gold quality
subcutaneous adipose tissue	UBERON:0002190	58.18	gold quality
saliva-secreting gland	UBERON:0001044	58.08	gold quality
adenohypophysis	UBERON:0002196	57.91	gold quality
left lobe of thyroid gland	UBERON:0001120	57.80	gold quality
mucosa of stomach	UBERON:0001199	57.72	gold quality
minor salivary gland	UBERON:0001830	57.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF9, NFATC1, RBPJ, TBX21

miRNA regulators (miRDB)

61 targeting PDCD1, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-3960	99.41	66.11	96
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4758-3P	99.12	63.96	869

Literature-anchored findings (GeneRIF, showing 40)

• PD-1 may play an important role in germinal center reactions (PMID:12095712)
• A regulatory polymorphism in this gene is associated with susceptibility to systemic lupus erythematosus in humans (p.666). (PMID:12402038)
• Modulation of immune responses to hPD-1 will depend upon the type of costimulatory signal delivered, the cytokine milieu, and the signaling pathways activated in the responding cell, be it T- or B-cell or monocyte. (PMID:12517932)
• Differential binding properties of B7-H1 and B7-DC to programmed death-1. (PMID:12893276)
• We investigated the existence of single-nucleotide polymorphisms (SNPs) in the PD-1 gene in patients with type 1 diabetes in comparison with healthy control subjects. (PMID:14617032)
• the association between lupus nephritis and PDCD1 was weaker in European American than in Swedish families (PMID:14730631)
• The PD-1 gene is significantly associated with rheumatoid arthritis susceptibility, suggesting the possibility that PD-1 may contribute to the pathogenesis of RA. (PMID:15022318)
• evidence of the involvement of the human PDCD1 gene in arthritis. (PMID:15188352)
• Our data indicate polymorphism in intron 4 of the PDCD1 gene affects the occurrence of APA and may slightly modify the risk of sporadic SLE. (PMID:15322919)
• 6867C/G sinsgle nucleotide polymorphism of the PD-1 gene is associated with lupus nephropathy in Caucasian SLE patients. (PMID:15352422)
• The PDCD1 gene is associated with renal manifestations(but not with susceptibility to)in systemic lupus erythematosus patients from northern Sweden. (PMID:15934088)
• description of four alternatively spliced PD-1 mRNA transcripts (PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2,3, and PD-1Deltaex2,3,4) in addition to the full length isoform (PMID:16171790)
• CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms. (PMID:16227604)
• dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes Sjogren syndrome (PMID:16265694)
• A novel role is demonstrated for PD-1 in inhibiting beta 1 and beta 2 integrin-mediated adhesion. (PMID:16278812)
• The genotype of PDCD1 gene 7809 locus was G/G in all indigenous Han Chinese, while the SNPs of PDCD1 gene 7872 locus and 8162 locus might affect the susceptibility to SLE development. (PMID:16471222)
• PD-1 has potential as a marker to discriminate between resting regulatory T cells and activated T cells, and to allow more homogeneous purification of these cells. (PMID:16493037)
• PD-1 in HIV-specific CD8+ T cells may have a role in reversible immune dysfunction (PMID:16917489)
• PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. (PMID:16954372)
• most hepatitis C virus (HCV)-specific CD8 cells expressed PD-1 at time of acute illness; expression declined with acquisition of memory phenotype & recovery of CD8 cell function; high levels were present when HCV persisted & CD8 cells were dysfunctional (PMID:16956940)
• Data suggest no association of polymorphisms with type 1 diabetes. (PMID:17130567)
• the genetic evaluation by association study demonstrated that the PD-1 gene was a predisposing gene to the development of T1D mellitus in the Japanese population (PMID:17203303)
• regulatory single nucleotide polymorphism PD1.3G/A was shown to be involved in susceptibility to childhood-onset systemic lupus erythematosus but not lupus nephritis. (PMID:17228327)
• PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion (PMID:17272504)
• Modulation of PD-1 system may play a role in the development of autoimmune liver diseases. (PMID:17311651)
• These results suggest that PDCD1 genetic variation influences the risk and expression of systemic lupus erythematosus and that these associations vary according to ethnic background. (PMID:17344889)
• We conclude that polymorphisms in the PDCD1 gene analyzed here are not associated with RA in a Japanese population. (PMID:17468813)
• These results show that small effects within PDCD1 may contribute towards the development of GD, supporting the hypothesis that much of the currently unknown genetic contribution to GD could be due to several small genetic effects with ORs 1.2. (PMID:17490403)
• Study demonstrates that the inhibitory molecule PD-1 is significantly upregulated on total and HCV-specific CD8(+) cytotoxic T cells in the peripheral blood and livers of patients with chronic infection. (PMID:17567698)
• 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)
• The interaction of PD-1 and its ligands is involved in the downregulation of autoreactive lymphocytes and the regulation of pathogenesis in autoimmune liver disease. (PMID:17610472)
• PD-1 expression on HIV-specific CD4-positive T cells in increased in chronic HIV infection and can be used as a phenotypic marker of the disease. (PMID:17641065)
• We demonstrated the expression of PD-1 on CD4+ neoplastic and non-neoplastic T-cells, and that of PD-L1 on the neoplastic cells in ATL patients. It is suggested that the PD-1/PD-L1 pathway may contribute to the marked immunodeficient state of ATL patients (PMID:17721918)
• PD-1 upregulation on HBV-specific CD8 T cells is engaged in the dysfunction of T cells and high viraemia in CHB patients, and the antiviral T-cell responses could be improved by the blockade of this inhibitory PD-1/PD-L1 pathway. (PMID:17868872)
• PD-1 expression on CD8 T cells, including those specific for HIV, can be related both to their differentiation stage and their activation status (PMID:17885290)
• 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)
• PD-1 demonstrates kinetics of synaptic accumulation, suggesting that the process involves T cell receptor-triggered cytoskeletal reorganization followed by ligand binding. (PMID:17968013)
• associated with susceptibility to systemic lupus erythematosus among Chinese (PMID:17999073)
• PD-1 might have a natural regulatory property behind myasthenia gravis. (PMID:18037500)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pdcd1	ENSMUSG00000026285
rattus_norvegicus	Pdcd1	ENSRNOG00000019043

Protein

Protein identifiers

Programmed cell death protein 1 — Q15116 (reviewed: Q15116)

All UniProt accessions (4): Q15116, A0A0M3M0G7, E7ER21, H0Y2W6

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self. Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2. Following T-cell receptor (TCR) engagement, PDCD1 associates with TCR-CD3 in the immunological synapse and directly inhibits T-cell activation. Suppresses T-cell activation through the recruitment of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated within the ITSM motif, leading to the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta. 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 CD274/PDCD1L1 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. Monomer.

Subcellular location. Cell membrane.

Post-translational modifications. Ubiquitinated at Lys-233 by the SCF(FBXO38) complex, leading to its proteasomal degradation. Ubiquitinated via ‘Lys-48’-linked polyubiquitin chains. Deubiquitinated and thus stabilized by USP5. Tyrosine phosphorylated at Tyr-223 (within ITIM motif) and Tyr-248 (ITSM motif) upon ligand binding. Phosphorylation at Tyr-248 by FYN promotes the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta. Phosphorylation at Thr-234 promotes the recruitment of the deubiquitinase USP5. N-glycosylation at Asn-58 contains at least two N-acetylglucosamine units and one fucose. N-glycosylation does not affect binding to nivolumab drug.

Disease relevance. Autoimmune disease, multisystem, infantile-onset, 4 (ADMIO4) [MIM:621004] An autosomal recessive immunologic disorder characterized by lymphoproliferative autoimmunity and onset of various autoimmune diseases in early childhood. Death from autoimmune pneumonitis may occur. The disease may be caused by variants affecting the gene represented in this entry. PDCD1 deficiency due to a homozygous frameshift mutation has been detected in a patient with severe tuberculosis and autoimmunity. The patient had depletion and dysfunction of multiple T and NK lymphocyte subsets and impaired gamma-IFN production.

Activity regulation. Inhibited by pembrolizumab (also named MK-3475 or lambrolizumab), a monoclonal antibody that prevents the interaction with CD274/PDCD1L1. Inhibited by nivolumab (also named ONO-4538, BMS-936558 or Opdivo), a monoclonal antibody that prevents the interaction with CD274/PDCD1L1. The interaction with nivolumab is not dependent on glycosylation and depends on a loop at the N-terminus (N-terminal loop, corresponding to residues 25-34). Targeting the interaction between PDCD1 and CD274/PDCD1L1 with pembrolizumab and nivolumab antibodies has demonstrated great promise as a strategy for controlling and eradicating cancer. Pembrolizumab and nivolumab are used for treatment of patients with advanced melanoma. These antibodies are also effective against other cancers, such as non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin’s lymphoma.

RefSeq proteins (1): NP_005009* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR042379	PDCD1	Family

Pfam: PF07686

UniProt features (51 total): strand 16, mutagenesis site 8, glycosylation site 4, region of interest 4, modified residue 3, short sequence motif 2, topological domain 2, sequence conflict 2, helix 2, signal peptide 1, chain 1, compositionally biased region 1, disulfide bond 1, cross-link 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6UMU	X-RAY DIFFRACTION	1.18
6J14	X-RAY DIFFRACTION	1.4
6UMV	X-RAY DIFFRACTION	1.42
7WSL	X-RAY DIFFRACTION	1.53
9EHT	X-RAY DIFFRACTION	1.54
7VUX	X-RAY DIFFRACTION	1.64
8EQ6	X-RAY DIFFRACTION	1.65
6K0Y	X-RAY DIFFRACTION	1.7
7E9B	X-RAY DIFFRACTION	1.78
9Q8L	X-RAY DIFFRACTION	1.85
8GY5	X-RAY DIFFRACTION	1.98
6UMT	X-RAY DIFFRACTION	1.99
5GGS	X-RAY DIFFRACTION	2
9HK1	X-RAY DIFFRACTION	2.03
3RRQ	X-RAY DIFFRACTION	2.1
6ROY	X-RAY DIFFRACTION	2.1
5B8C	X-RAY DIFFRACTION	2.15
6HIG	X-RAY DIFFRACTION	2.2
5WT9	X-RAY DIFFRACTION	2.4
4ZQK	X-RAY DIFFRACTION	2.45
6JBT	X-RAY DIFFRACTION	2.47
8U32	X-RAY DIFFRACTION	2.51
6XKR	X-RAY DIFFRACTION	2.59
6J15	X-RAY DIFFRACTION	2.6
8U31	X-RAY DIFFRACTION	2.73
7CU5	X-RAY DIFFRACTION	2.81
5IUS	X-RAY DIFFRACTION	2.89
6ROZ	X-RAY DIFFRACTION	2.89
5JXE	X-RAY DIFFRACTION	2.9
6JJP	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15116-F1	74.53	0.36

Antibody-complex structures (SAbDab): 27 — 5B8C, 5GGR, 5GGS, 5JXE, 5WT9, 6HIG, 6J14, 6J15, 6JBT, 6JJP, 6K0Y, 6XKR, 7BXA, 7CGW, 7CU5, 7E9B, 7VUX, 7WSL, 7WVM, 8AS0, 8EQ6, 8GY5, 8U31, 8U32, 9EHT (+2 more)

Functional residue map

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

Post-translational modifications (4): 223, 234, 248, 233

Disulfide bonds (1): 54–123

Glycosylation sites (4): 49, 58, 74, 116

Mutagenesis-validated functional residues (8):

Position	Phenotype
49	decreased n-glycosylation without affecting binding to binding to nivolumab drug.
58	decreased n-glycosylation without affecting binding to binding to nivolumab drug.
74	decreased n-glycosylation without affecting binding to binding to nivolumab drug.
116	decreased n-glycosylation without affecting binding to binding to nivolumab drug.
210	does not affect ubiquitination by the scf(fbxo38) complex.
223	reduced tyrosine phosphorylation without affecting ability to mediate recruitment of ptpn11/shp-2.
233	abolishes ubiquitination by the scf(fbxo38) complex.
248	reduced tyrosine phosphorylation. abolished ability to mediate recruitment of ptpn11/shp-2.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-389948	Co-inhibition by PD-1
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane

MSigDB gene sets: 401 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_REGULATION_OF_TOLERANCE_INDUCTION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (16): B cell apoptotic process (GO:0001783), adaptive immune response (GO:0002250), negative regulation of tolerance induction (GO:0002644), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), negative regulation of B cell apoptotic process (GO:0002903), apoptotic process (GO:0006915), humoral immune response (GO:0006959), negative regulation of inflammatory response (GO:0050728), regulation of immune response (GO:0050776), negative regulation of immune response (GO:0050777), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), positive regulation of T cell apoptotic process (GO:0070234), regulatory T cell apoptotic process (GO:1902482), immune system process (GO:0002376), negative regulation of multicellular organismal process (GO:0051241)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of T cell activation by CD28 family	1
SARS-CoV Infections	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	4
negative regulation of immune system process	2
T cell apoptotic process	2
lymphocyte apoptotic process	1
tolerance induction	1
regulation of tolerance induction	1
negative regulation of developmental process	1
negative regulation of multicellular organismal process	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
B cell apoptotic process	1
regulation of B cell apoptotic process	1
negative regulation of lymphocyte apoptotic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
regulation of immune system process	1
regulation of response to stimulus	1
negative regulation of response to stimulus	1
regulation of immune response	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
negative regulation of leukocyte cell-cell adhesion	1
positive regulation of lymphocyte apoptotic process	1
regulation of T cell apoptotic process	1
biological_process	1
multicellular organismal process	1
negative regulation of biological process	1
regulation of multicellular organismal process	1
signaling receptor activity	1

Protein interactions and networks

STRING

2840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD1	PDCD1LG2	Q9BQ51	999
PDCD1	CD274	Q9NZQ7	999
PDCD1	CD80	P33681	997
PDCD1	CD86	P42081	996
PDCD1	CTLA4	P16410	990
PDCD1	PTPN11	Q06124	973
PDCD1	LGALS9	O00182	968
PDCD1	LGALS9B	Q3B8N2	947
PDCD1	LGALS9C	Q6DKI2	947
PDCD1	LAG3	P18627	930
PDCD1	ICOS	Q9Y6W8	929
PDCD1	CD28	P10747	929
PDCD1	CD8A	P01732	929
PDCD1	CD4	P01730	920
PDCD1	MTUS1	Q9ULD2	884
PDCD1	BTLA	Q7Z6A9	884

IntAct

58 interactions, top by confidence:

A	B	Type	Score
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
PDCD1LG2	PDCD1	psi-mi:“MI:0407”(direct interaction)	0.850
PDCD1	PDCD1LG2	psi-mi:“MI:0407”(direct interaction)	0.850
PDCD1	PDCD1LG2	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (131): C20orf24 (Affinity Capture-MS), POP5 (Affinity Capture-MS), SFXN3 (Affinity Capture-MS), SLC25A23 (Affinity Capture-MS), DAGLB (Affinity Capture-MS), SMDT1 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), DENND6A (Affinity Capture-MS), SLC25A28 (Affinity Capture-MS), INTS4 (Affinity Capture-MS), C4orf29 (Affinity Capture-MS), FAM127A (Affinity Capture-MS), INTS7 (Affinity Capture-MS), SLC25A16 (Affinity Capture-MS), DCP2 (Affinity Capture-MS)

ESM2 similar proteins: A8MVS5, O18796, O54693, O75462, O88507, P07722, P08887, P09564, P15151, P19438, P20916, P20917, P26992, P29590, P32506, P38484, P41155, P50555, P70225, Q01113, Q08406, Q13477, Q14626, Q14CZ8, Q15116, Q29RN8, Q4V892, Q4V9Z5, Q5DRQ8, Q5RF19, Q61190, Q62522, Q64385, Q6BAA4, Q6UXD5, Q71DR4, Q7Z692, Q86YD3, Q8BQC3, Q8IVU1

Diamond homologs: Q02242, Q15116, P01672

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
nivolumab	“down-regulates activity”	PDCD1	binding
pembrolizumab	“down-regulates activity”	PDCD1	binding
PDCD1	“down-regulates activity”	DNM1L
PDCD1	“down-regulates activity”	AKT
PDCD1	“down-regulates activity”	MEK1/2
PDCD1	“down-regulates activity”	ERK1/2
PDCD1	up-regulates	“T cell exhaustion”
PTPN11	“down-regulates activity”	PDCD1	dephosphorylation
CDK1	“down-regulates quantity by destabilization”	PDCD1	phosphorylation
SCF-FBW7	“down-regulates quantity by destabilization”	PDCD1	polyubiquitination
CD274	up-regulates	PDCD1	binding
hsa-miR-138-5p	“down-regulates quantity by repression”	PDCD1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PIP3 activates AKT signaling	5	22.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
T cell costimulation	6	149.8×	3e-10
negative regulation of T cell receptor signaling pathway	6	146.5×	3e-10
negative regulation of T cell proliferation	5	110.1×	9e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	14
Likely benign	7
Benign	17

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3376502	PDCD1, 1-BP DUP, 105C	Pathogenic

SpliceAI

688 predictions. Top by Δscore:

Variant	Effect	Δscore
2:241851295:CTT:C	acceptor_gain	1.0000
2:241851298:C:CC	acceptor_gain	1.0000
2:241851299:T:C	acceptor_gain	1.0000
2:241851300:T:C	acceptor_gain	1.0000
2:241851300:T:TC	acceptor_gain	1.0000
2:241851944:CTCA:C	donor_loss	1.0000
2:241851945:TCA:T	donor_loss	1.0000
2:241852192:CGTTA:C	donor_loss	1.0000
2:241852193:GTTA:G	donor_loss	1.0000
2:241852194:TTAC:T	donor_loss	1.0000
2:241852195:TAC:T	donor_loss	1.0000
2:241852350:CTCT:C	acceptor_gain	1.0000
2:241852351:TCTC:T	acceptor_loss	1.0000
2:241852352:CT:C	acceptor_gain	1.0000
2:241852353:TC:T	acceptor_loss	1.0000
2:241852354:C:CC	acceptor_gain	1.0000
2:241852354:CTGG:C	acceptor_loss	1.0000
2:241852355:T:A	acceptor_loss	1.0000
2:241852615:CCGCA:C	donor_loss	1.0000
2:241852616:CGCA:C	donor_loss	1.0000
2:241852620:CCTG:C	donor_gain	1.0000
2:241852622:TGTC:T	donor_gain	1.0000
2:241851293:TCCTT:T	acceptor_gain	0.9900
2:241851294:CCTTC:C	acceptor_gain	0.9900
2:241851295:CTTCT:C	acceptor_loss	0.9900
2:241851296:TT:T	acceptor_gain	0.9900
2:241851297:TC:T	acceptor_loss	0.9900
2:241851298:C:CG	acceptor_loss	0.9900
2:241851299:T:A	acceptor_loss	0.9900
2:241851299:T:TC	acceptor_gain	0.9900

AlphaMissense

1846 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:241852739:G:C	F106L	0.996
2:241852739:G:T	F106L	0.996
2:241852741:A:G	F106L	0.996
2:241852902:A:G	F52S	0.996
2:241852696:A:C	Y121D	0.994
2:241852851:C:G	R69P	0.994
2:241852902:A:C	F52C	0.994
2:241852680:A:G	I126T	0.993
2:241852689:C:G	C123S	0.993
2:241852690:A:T	C123S	0.993
2:241852858:A:G	W67R	0.993
2:241852858:A:T	W67R	0.993
2:241852646:G:C	S137R	0.992
2:241852646:G:T	S137R	0.992
2:241852648:T:G	S137R	0.992
2:241852823:C:A	K78N	0.992
2:241852823:C:G	K78N	0.992
2:241852632:A:T	L142H	0.991
2:241852695:T:C	Y121C	0.991
2:241852859:G:C	N66K	0.991
2:241852859:G:T	N66K	0.991
2:241852901:G:C	F52L	0.991
2:241852901:G:T	F52L	0.991
2:241852903:A:G	F52L	0.991
2:241852707:T:C	D117G	0.990
2:241852772:G:C	F95L	0.990
2:241852772:G:T	F95L	0.990
2:241852774:A:G	F95L	0.990
2:241852896:C:G	C54S	0.990
2:241852897:A:T	C54S	0.990

dbSNP variants (sampled 300 via entrez): RS1000249974 (2:241852874 C>A,T), RS1000309869 (2:241857398 T>G), RS1000350301 (2:241857216 C>A,T), RS1000554864 (2:241856991 A>G), RS1000853745 (2:241853956 C>T), RS1001218796 (2:241857208 A>C), RS1001286200 (2:241853753 A>G), RS1001890806 (2:241854892 G>A), RS1001945649 (2:241856015 T>C), RS1001990276 (2:241849672 G>A,C), RS1002041146 (2:241850002 A>C,T), RS1002261373 (2:241855097 G>A), RS1002324748 (2:241859275 C>T), RS1002386347 (2:241859197 G>A,T), RS1002648007 (2:241859357 C>G,T)

Disease associations

OMIM: gene MIM:600244 | disease phenotypes: MIM:621004

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown
autoimmune disease with susceptibility to mycobacterium tuberculosis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autoimmune disease	Limited	AR

Mondo (2): autoimmune disease with susceptibility to mycobacterium tuberculosis (MONDO:0975847), systemic lupus erythematosus (MONDO:0007915)

Orphanet (0):

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000403	Recurrent otitis media
HP:0000488	Retinopathy
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002878	Respiratory failure
HP:0002958	Immune dysregulation
HP:0003237	Increased circulating IgG concentration
HP:0003261	Increased circulating IgA concentration
HP:0003453	Antineutrophil antibody positivity
HP:0003493	Antinuclear antibody positivity
HP:0005421	Decreased circulating complement C3 concentration

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003044_38	Crohn’s disease	1.000000e-09
GCST90002381_129	Eosinophil count	5.000000e-10
GCST90002382_93	Eosinophil percentage of white cells	1.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3307223 (SINGLE PROTEIN), CHEMBL4523993 (PROTEIN COMPLEX), CHEMBL5482985 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 30,351 (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
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL444633	RIFABUTIN	4	27,819
CHEMBL5095237	EVIXAPODLIN	1	735

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (18 total), top 18:

Ligand	Action	Affinity	Parameter
zimberelimab	Binding	10.76	pKd
cadonilimab	Binding	10.29	pEC50
rosnilimab	Agonist	10.29	pKd
nivolumab	Binding	10.28	pEC50
penpulimab	Binding	10.23	pKd
finotonlimab	Binding	10.19	pKd
pucolentimab	Binding	10.12	pKd
pembrolizumab	Binding	10.0	pKd
tislelizumab	Binding	9.82	pKd
prolgolimab	Binding	9.72	pKd
spartalizumab	Binding	9.7	pKd
sintilimab	Binding	9.6	pKd
lorigerlimab	Binding	9.38	pEC50
AUNP-12	Binding	9.14	pEC50
retifanlimab	Binding	8.82	pKd
cemiplimab	Binding	8.21	pKd
serplulimab	Antagonist	8.19	pIC50
toripalimab	Binding	7.68	pEC50

Binding affinities (BindingDB)

218 measured of 482 human assays (482 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
(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
(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
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
US20250340529, Compound 338	IC50	1.46 nM	US-20250340529: Heterocyclic Compounds as Immunomodulators of PD-L1 Interactions
(5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[(2-methyl-1H-indol-5-yl)methylamino]methyl]-2-pyridinyl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one	IC50	1.65 nM	US-10710986: PD-1/PD-L1 inhibitors
(2S)-2-[[5-chloro-2-[[1-(cyanomethyl)pyrazol-4-yl]methoxy]-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]phenyl]methylamino]-3-hydroxy-2-methylpropanoic acid	IC50	1.7 nM	US-20250230153

ChEMBL bioactivities

4633 potent at pChembl≥5 of 4698 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
10.49	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
10.19	IC50	0.064	nM	CHEMBL6018799

PubChem BioAssay actives

1301 with measured affinity, of 2327 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
(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
(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
(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
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
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
(4S)-5-amino-4-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-bis[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-4-amino-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-5-oxopentanoic acid	2017896: Inhibition of PD-I/PD-L2 interaction (unknown origin) expressed in human MDA-MB-23 cells	ec50	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)-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
(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
N-[2-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methylamino]ethyl]acetamide	1777326: Inhibition of human PD1/PDL1 protein-protein interaction assessed as undissociated complex after 2 hrs by HTRF assay	ic50	0.0008	uM
[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol	1516541: Inhibition of human Fc-tagged PD1 N-terminal domain (Leu25 to Gln167 residues) expressed in HEK293 cells/human His-tagged PDL1 (Phe19 to Arg238 residues) expressed in HEK293 cells protein-protein interaction after 1 hr by APC-labeled anti-His antibody/Eu-labeled anti-human IgG based HTRF assay	ic50	0.0009	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-(2-hydroxyethyl)piperidine-2-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0009	uM
3-[[6-[3-(2-fluorophenyl)-2-methylphenyl]-2-methoxy-3-pyridinyl]methylamino]propanamide	2017914: Inhibition of PD-I/PD-L1 interaction (unknown origin) by HTRF assay	ic50	0.0009	uM
1-[[4-[2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxyphenyl]methyl]-N-hydroxypyrrolidine-3-carboxamide	1978454: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay	ic50	0.0009	uM
(2-methyl-3-phenylphenyl)methanol	1516541: Inhibition of human Fc-tagged PD1 N-terminal domain (Leu25 to Gln167 residues) expressed in HEK293 cells/human His-tagged PDL1 (Phe19 to Arg238 residues) expressed in HEK293 cells protein-protein interaction after 1 hr by APC-labeled anti-His antibody/Eu-labeled anti-human IgG based HTRF assay	ic50	0.0009	uM
N-[2-chloro-3-[3-[[5-[(2S)-2-hydroxypropyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carbonyl]amino]-2-methylphenyl]phenyl]-1,5-dimethyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carboxamide	2035657: Inhibition of PD-1/PD-L1 interaction (unknown origin) incubated for 24 hrs by HTRF assay	ic50	0.0010	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	decreases expression	1
disitamab vedotin	affects reaction, increases response to substance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
Indirubin E804	decreases expression	1
7-bromoindirubin-3’-oxime	affects cotreatment, decreases expression	1
6,2’,4’-trimethoxyflavone	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Abacavir	increases expression, increases response to substance	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Biological Factors	increases expression	1
Lead	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Methapyrilene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Zearalenone	increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

327 unique, capped per target: 327 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4184946	Binding	Inhibition of His-tagged PD-L1 binding to PD-1-Ig (unknown origin) preincubated with PD-L1 for 15 mins followed by PD-1-Ig addition measured after 15 mins by HTRF binding assay	Small molecule immuno-oncology therapeutic agents. — Bioorg Med Chem Lett

Cellosaurus cell lines

15 cell lines: 9 cancer cell line, 4 spontaneously immortalized cell line, 1 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AD	Raji-hPD-1	Cancer cell line	Male
CVCL_B2A4	Abcam HeLa PDCD1 KO	Cancer cell line	Female
CVCL_B8M7	Abcam HCT 116 PDCD1 KO	Cancer cell line	Male
CVCL_B9A2	Abcam MCF-7 PDCD1 KO	Cancer cell line	Female
CVCL_B9PE	Abcam A-549 PDCD1 KO	Cancer cell line	Male
CVCL_C9D9	KSCBi005-A-9	Induced pluripotent stem cell	Male
CVCL_D7BR	Abeomics CHO-K1 PD-1	Spontaneously immortalized cell line	Female
CVCL_D7J0	Ubigene 786-O PDCD1 KO	Cancer cell line	Male
CVCL_E3JE	Jurkat-Lucia TCR-hPD-1	Cancer cell line	Male
CVCL_E5I9	Daudi/PD-1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients