Target Information

Target General Information

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Target ID

T59631 (Former ID: TTDNC00489)

Target Name

Programmed cell death protein 1 (PD-1)

Synonyms

hPD1; hPD-1; Protein PD1; Protein PD-1; PD1; CD279

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Gene Name

PDCD1

Target Type

Successful target

[1]

Disease

[+] 8 Target-related Diseases

Demodex blepharitis ICD-11: 1G07

Endometrial cancer [ICD-11: 2C76]

Hodgkin lymphoma [ICD-11: 2B30]

Lung cancer [ICD-11: 2C25]

Melanoma [ICD-11: 2C30]

Nasopharyngeal cancer ICD-11: 2B6B

Stomach cancer [ICD-11: 2B72]

Ureteral cancer [ICD-11: 2C92]

Function

Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2. Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR 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. Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self.

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BioChemical Class

Immunoglobulin

UniProt ID

PDCD1_HUMAN

Sequence

MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS
ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT
YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGS
LVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVP
CVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 6 Approved Drugs

Cemiplimab

Drug Info

Approved

Cutaneous squamous cell carcinoma

[4]

MK-3475

Drug Info

Approved

Melanoma

[1], [5]

Nivolumab

Drug Info

Approved

Melanoma

[6], [7]

Pembrolizumab

Drug Info

Approved

Melanoma

[8], [9]

Retifanlimab

Drug Info

Approved

Neuroendocrine cancer

[10]

Tislelizumab

Drug Info

Approved

Hodgkin lymphoma

[11]

Clinical Trial Drug(s)

[+] 17 Clinical Trial Drugs

BGB-A317

Drug Info

Phase 3

Hepatocellular carcinoma

[17]

IBI-308

Drug Info

Phase 3

Bronchioalveolar carcinoma

[9]

INCSHR1210

Drug Info

Phase 3

Bronchioalveolar carcinoma

[9]

PDR001

Drug Info

Phase 3

Melanoma

[18]

Spartalizumab

Drug Info

Phase 3

Melanoma

[9]

JNJ 63723283

Drug Info

Phase 2

Ulcerative colitis

[9]

M7824

Drug Info

Phase 2

Solid tumour/cancer

[17], [20]

MGD013

Drug Info

Phase 1/2

Hepatocellular carcinoma

[30]

AMP-224

Drug Info

Phase 1

Solid tumour/cancer

[45]

BI-754091

Drug Info

Phase 1

Solid tumour/cancer

[9]

CC-90006

Drug Info

Phase 1

Psoriasis vulgaris

[46]

GSK2661380

Drug Info

Phase 1

Solid tumour/cancer

[45]

LZM009

Drug Info

Phase 1

Solid tumour/cancer

[9]

MEDI0680

Drug Info

Phase 1

Solid tumour/cancer

[47]

PF-06801591

Drug Info

Phase 1

Solid tumour/cancer

[9]

Sym021

Drug Info

Phase 1

Solid tumour/cancer

[9]

TSR-042

Drug Info

Phase 1

Solid tumour/cancer

[9]

Patented Agent(s)

[+] 9 Patented Agents

1,2,4-oxadiazole derivative 1

Drug Info

Patented

Solid tumour/cancer

[48]

1,2,4-oxadiazole derivative 2

Drug Info

Patented

Solid tumour/cancer

[48]

1,3,4-oxadiazole derivative 1

Drug Info

Patented

Solid tumour/cancer

[48]

1,3,4-oxadiazole derivative 2

Drug Info

Patented

Solid tumour/cancer

[48]

Cyclic compound 1

Drug Info

Patented

Solid tumour/cancer

[48]

Cyclic compound 2

Drug Info

Patented

Solid tumour/cancer

[48]

Cyclic compound 3

Drug Info

Patented

Solid tumour/cancer

[48]

PMID30107136-Compound-Example15

Drug Info

Patented

Solid tumour/cancer

[48]

PMID30107136-Compound-Example16

Drug Info

Patented

Solid tumour/cancer

[48]

Mode of Action

[+] 4 Modes of Action

Modulator

[+] 3 Modulator drugs

Cemiplimab

Drug Info

[4]

Nivolumab

Drug Info

[1]

AMP-224

Drug Info

[49]

Inhibitor

[+] 21 Inhibitor drugs

Retifanlimab

Drug Info

[9], [20]

BGB-A317

Drug Info

[20]

INCSHR1210

Drug Info

[20]

GSK2661380

Drug Info

[50]

1,2,4-oxadiazole derivative 1

Drug Info

[48]

1,2,4-oxadiazole derivative 2

Drug Info

[48]

1,3,4-oxadiazole derivative 1

Drug Info

[48]

1,3,4-oxadiazole derivative 2

Drug Info

[48]

Cyclic compound 1

Drug Info

[48]

Cyclic compound 2

Drug Info

[48]

Cyclic compound 3

Drug Info

[48]

PMID30107136-Compound-Example15

Drug Info

[48]

PMID30107136-Compound-Example16

Drug Info

[48]

AUNP-12

Drug Info

[9]

PMID30247903-Compound-General structure17

Drug Info

[9]

PMID30247903-Compound-General structure20

Drug Info

[9]

PMID30247903-Compound-General structure21

Drug Info

[9]

PMID30247903-Compound-General structure22

Drug Info

[9]

PMID30247903-Compound-General structure23

Drug Info

[9]

PMID30247903-Compound-General structure24

Drug Info

[9]

PMID30247903-Compound-General structure25

Drug Info

[9]

Antagonist

[+] 2 Antagonist drugs

PDR001

Drug Info

[46]

CC-90006

Drug Info

[46]

antagonist

[+] 3 antagonist drugs

PMID30247903-Compound-General structure13

Drug Info

[9]

PMID30247903-Compound-General structure14

Drug Info

[9]

PMID30247903-Compound-General structure15

Drug Info

[9]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: (2S,3R)-2-azaniumyl-3-hydroxybutanoate

Ligand Info

Structure Description

Complex structure of PD1 and 609A-Fab

PDB:7VUX

Method

X-ray diffraction

Resolution

1.64 Å

Mutation

[51]

PDB Sequence

MWNPPTFSPA

⁴⁰

LLVVTEGDNA

⁵⁰

TFTCSFSNTS

⁶⁰

ESFVLNWYRM

⁷⁰

SPSNQTDKLA

⁸⁰

AFPEDRSQPG

⁹⁰

QDSRFRVTQL

¹⁰⁰

PNGRDFHMSV

¹¹⁰

VRARRNDSGT

¹²⁰

YLCGAISLAP

¹³⁰

KAQIKESLRA

¹⁴⁰

ELRVTERRAE

¹⁵⁰

Residue

Distance (Å)

VAL151

3.837

Residue

Distance (Å)

PRO152

1.609

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target
Cell adhesion molecules	hsa04514	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	1.51E-05
Closeness centrality	2.10E-01	Radiality	1.37E+01	Clustering coefficient	7.14E-01
Neighborhood connectivity	3.14E+01	Topological coefficient	2.20E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Cell adhesion molecules (CAMs)

T cell receptor signaling pathway

Reactome

[+] 1 Reactome Pathways

PD-1 signaling

WikiPathways

[+] 2 WikiPathways

T-Cell Receptor and Co-stimulatory Signaling

Costimulation by the CD28 family

References

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REF 1

2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services.

REF 3

Sintilimab: First Global Approval. Drugs. 2019 Feb;79(3):341-346.

REF 4

2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7499).

REF 6

REF 7

Nivolumab, a Novel Anti D-1 Monoclonal Antibody for the Treatment of Solid and Hematologic Malignancies (Personalized Medicine in Oncology). Emma Thornton. Anti-PD-1 Therapy. June 2014

REF 8

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 9

Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway.J Med Chem. 2019 Feb 28;62(4):1715-1730.

REF 10

FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 761334.

REF 11

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC). Expert Opin Investig Drugs. 2020 Dec;29(12):1355-1364.

REF 12

Toripalimab: the First Domestic Anti-Tumor PD-1 Antibody in China. Front Immunol. 2022 Jan 12;12:730666.

REF 13

ClinicalTrials.gov (NCT04165317) Study of Sasanlimab (PF-06801591) in Combination With Bacillus Calmette-Guerin (BCG) in Participants With High-Risk Non-Muscle Invasive Bladder Cancer (CREST). U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT04194775) A Multi-Center, Double-Blind, Randomized, Phase III Study to Investigate the Efficacy and Safety of Nofazinlimab (CS1003) in Combination With Lenvatinib Compared to Placebo in Combination With Lenvatinib as First-Line Therapy in Subjects With Advanced Hepatocellular Carcinoma (HCC). U.S.National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT00308867) Photodynamic Therapy With PD P 506 A or Its Placebo Compared With Cryosurgery for the Treatment of Mild to Moderate Actinic Keratosis. U.S.National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT04943627) A Phase 3 Trial of Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer After Platinum-Based Chemotherapy (BRAVA). U.S.National Institutes of Health.

REF 17

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 18

ClinicalTrials.gov (NCT02967692) A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (COMBI-i). U.S. National Institutes of Health.

REF 19

ClinicalTrials.gov (NCT04785820) A Study of RO7121661 and RO7247669 Compared With Nivolumab in Participants With Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus. U.S. National Institutes of Health.

REF 20

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 21

ClinicalTrials.gov (NCT04549025) Study of PD-1 Inhibitor JTX-4014 Alone and in Combination With Vopratelimab in Biomarker-selected Subjects With Metastatic NSCLC After One Prior Platinum-containing Regimen (SELECT). U.S. National Institutes of Health.

REF 22

ClinicalTrials.gov (NCT04380805) A Study of AK104, a PD-1/CTLA-4 Bispecific Antibody in Subjects With Recurrent/Metastatic Cervical Cancer. U.S. National Institutes of Health.

REF 23

ClinicalTrials.gov (NCT05516758) A Phase 2b, Double-Blind, Placebo-Controlled Study to Evaluate Peresolimab in Adult Participants With Moderately-to-Severely Active Rheumatoid Arthritis. U.S.National Institutes of Health.

REF 24

ClinicalTrials.gov (NCT05848011) A Phase 2, Randomized, Open-Label, Study of Lorigerlimab With Docetaxel or Docetaxel Alone in Participants With Metastatic Castration-Resistant Prostate Cancer. U.S.National Institutes of Health.

REF 25

ClinicalTrials.gov (NCT05216835) A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD7789, an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma. U.S.National Institutes of Health.

REF 26

ClinicalTrials.gov (NCT05584670) A Phase 1/2, Open Label, First-in-human, Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics, and Anti-tumor Activity of SAR445877 Administered as Monotherapy in Adults With Advanced Solid Tumors. U.S.National Institutes of Health.

REF 27

ClinicalTrials.gov (NCT05005728) Phase 2 Multiple-Dose, Multiple-Arm, Parallel Assignment Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of XmAb?20717 Alone or in Combination With Chemotherapy or Targeted Therapies in Selected Subjects With Metastatic Castration-Resistant Prostate Cancer. U.S.National Institutes of Health.

REF 28

ClinicalTrials.gov (NCT02908906) A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of JNJ-63723283, an Anti-PD-1 Monoclonal Antibody, in Participants With Advanced Cancers. U.S. National Institutes of Health.

REF 29

ClinicalTrials.gov (NCT04995523) Phase I/II, Open-label, Dose Escalation and Dose Expansion Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD2936 Anti-TIGIT/Anti-PD-1 Bispecific Antibody in Participants With Advanced or Metastatic NSCLC. U.S.National Institutes of Health.

REF 30

ClinicalTrials.gov (NCT04212221) MGD013 Monotherapy and Combination With Brivanib Dose Escalation and Expansion Study in Advanced Liver Cancer Patients. U.S. National Institutes of Health.

REF 31

ClinicalTrials.gov (NCT04303858) A Study to Evaluate Safety and Anti-Tumor Activity of RO7284755 Alone or in Combination With Atezolizumab in Participants With Advanced and/or Metastatic Solid Tumors. U.S. National Institutes of Health.

REF 32

ClinicalTrials.gov (NCT03853109) AMG 404 in Patients With Advanced Solid Tumors.. U.S. National Institutes of Health.

REF 33

ClinicalTrials.gov (NCT04363242) A Study to Find the Maximum Tolerated Dose (MTD) of SYN125 in People With Solid Tumors and the MTD of SYN125 With a Fixed Dose of SYN004 in People With Cancer of the Internal or External Lining of the Body.. U.S. National Institutes of Health.

REF 34

ClinicalTrials.gov (NCT03950297) Phase 1, First in Human, Open-Label, Dose-Escalation Study of 609A. U.S. National Institutes of Health.

REF 35

ClinicalTrials.gov (NCT03053466) APL-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors. U.S. National Institutes of Health.

REF 36

ClinicalTrials.gov (NCT02952248) A Trial to Find and Investigate a Safe Dose of a New Substance (BI 754091) for Patients With Solid Tumours. U.S. National Institutes of Health.

REF 37

ClinicalTrials.gov (NCT03530397) A Study to Evaluate MEDI5752 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 38

ClinicalTrials.gov (NCT03761017) MGD019 DART Protein in Unresectable/Metastatic Cancer. U.S. National Institutes of Health.

REF 39

ClinicalTrials.gov (NCT03752398) A Study of XmAb23104 in Subjects With Selected Advanced Solid Tumors (DUET-3) (DUET-3). U.S. National Institutes of Health.

REF 40

ClinicalTrials.gov (NCT04140500) Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors. U.S. National Institutes of Health.

REF 41

ClinicalTrials.gov (NCT04777084) The Efficacy and Safety of the Bispecific Anti-PD-1/PD-L1 Antibody IBI318 Combined With Lenvatinib in NSCLC.. U.S. National Institutes of Health.

REF 42

ClinicalTrials.gov (NCT04606472) A Study of SI-B003, a PD-1/CTLA-4 Bispecific Antibody, in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 43

Clinical pipeline report, company report or official report of Novartis.

REF 44

ClinicalTrials.gov (NCT04440943) A Study of the PD-L1xCD27 Bispecific Antibody CDX-527 in Patients With Advanced Malignancies. U.S. National Institutes of Health.

REF 45

ClinicalTrials.gov (NCT01352884) Study to Assess the Safety, Tolerability, and Pharmacokinetics of AMP-224 in Patients With Advanced Cancer. U.S. National Institutes of Health.

REF 46

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 47

A Phase Ib/II open-label study to evaluate the safety and efficacy of MEDI-551 in combination with immunomodulating therapy in patients with relapsed or refractory aggressive B cell lymphomas. J Immunother Cancer. 2014; 2(Suppl 3): P73.

REF 48

A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018).Expert Opin Ther Pat. 2018 Sep;28(9):665-678.

REF 49

National Cancer Institute Drug Dictionary (drug id 700595).

REF 50

REF 51

A strategy for the efficient construction of anti-PD1-based bispecific antibodies with desired IgG-like properties. MAbs. 2022 Jan-Dec;14(1):2044435.

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