Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T99948
(Former ID: TTDNC00468)
|
|||||
| Target Name |
Programmed cell death 1 ligand 1 (PD-L1)
|
|||||
| Synonyms |
hPD-L1; Programmed death ligand 1; PDL1; PDCD1LG1; PDCD1L1; PDCD1 ligand 1; B7H1; B7-H1; B7 homolog 1
Click to Show/Hide
|
|||||
| Gene Name |
CD274
|
|||||
| Target Type |
Successful target
|
[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Neuroendocrine carcinoma [ICD-11: 2C34] | |||||
| 2 | Non-small-cell lung cancer [ICD-11: 2C25] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 4 | Ureteral cancer [ICD-11: 2C92] | |||||
| Function |
As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response. Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10). Plays a critical role in induction and maintenance of immune tolerance to self.
Click to Show/Hide
|
|||||
| BioChemical Class |
Immunoglobulin
|
|||||
| UniProt ID | ||||||
| Sequence |
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEME
DKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGG ADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTT TTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTH LVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T32PI2 | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
| 1 | Avelumab | Drug Info | Approved | Merkel cell carcinoma | [4], [5] | |
| 2 | Durvalumab | Drug Info | Approved | Urothelial carcinoma | [4], [6] | |
| 3 | RG-7446 | Drug Info | Approved | Urothelial carcinoma | [7] | |
| Clinical Trial Drug(s) | [+] 10 Clinical Trial Drugs | + | ||||
| 1 | MEDI4736 | Drug Info | Phase 3 | Solid tumour/cancer | [14], [15] | |
| 2 | KN035 | Drug Info | Phase 2 | Solid tumour/cancer | [19] | |
| 3 | M7824 | Drug Info | Phase 2 | Solid tumour/cancer | [20], [21] | |
| 4 | Pidilizumab | Drug Info | Phase 2 | Diffuse large B-cell lymphoma | [22], [23], [24] | |
| 5 | Anti-PD-L1 | Drug Info | Phase 1 | Solid tumour/cancer | [42] | |
| 6 | C-Met/PD-L1 CAR-T Cell | Drug Info | Phase 1 | Hepatocellular carcinoma | [43] | |
| 7 | CA-170 | Drug Info | Phase 1 | Lymphoma | [20] | |
| 8 | FAZ053 | Drug Info | Phase 1 | Solid tumour/cancer | [20] | |
| 9 | LY3300054 | Drug Info | Phase 1 | Solid tumour/cancer | [16] | |
| 10 | MSB2311 | Drug Info | Phase 1 | Solid tumour/cancer | [16] | |
| Patented Agent(s) | [+] 1 Patented Agents | + | ||||
| 1 | PMID30107136-Compound-Example2 | Drug Info | Patented | Solid tumour/cancer | [44] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Durvalumab | Drug Info | [46] | |||
| 2 | MEDI4736 | Drug Info | [47] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | M7824 | Drug Info | [20] | |||
| 2 | CA-170 | Drug Info | [20] | |||
| 3 | FAZ053 | Drug Info | [21] | |||
| 4 | PMID30107136-Compound-Example2 | Drug Info | [44] | |||
| 5 | CA-327 | Drug Info | [16] | |||
| 6 | PMID30247903-Compound-General structure12 | Drug Info | [16] | |||
| 7 | PMID30247903-Compound-General structure5 | Drug Info | [16] | |||
| 8 | PMID30247903-Compound-General structure6 | Drug Info | [16] | |||
| 9 | PMID30247903-Compound-General structure7 | Drug Info | [16] | |||
| 10 | PMID30247903-Compound-General structure8 | Drug Info | [16] | |||
| 11 | PMID30247903-Compound-General structure9 | Drug Info | [16] | |||
| CAR-T-Cell-Therapy(Dual specific) | [+] 1 CAR-T-Cell-Therapy(Dual specific) drugs | + | ||||
| 1 | C-Met/PD-L1 CAR-T Cell | Drug Info | [43] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: PMID30107136-Compound-Example1 | Ligand Info | |||||
| Structure Description | Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor | PDB:5J89 | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [50] |
| PDB Sequence |
AFTVTVPKDL
27 YVVEYGSNMT37 IECKFPVEKQ47 LDLAALIVYW57 EMEDKNIIQF67 VHGEEDLKVQ 77 HSSYRQRARL87 LKDQLSLGNA97 ALQITDVKLQ107 DAGVYRCMIS117 YGGADYKRIT 127 VKVNAPYAAA137 LEHHH
|
|||||
|
|
||||||
| Ligand Name: N-({2,6-dimethoxy-4-[(2-methyl[1,1'-biphenyl]-3-yl)methoxy]phenyl}methyl)-D-alanine | Ligand Info | |||||
| Structure Description | IgV-V76T BMS compound 105 | PDB:6NM8 | ||||
| Method | X-ray diffraction | Resolution | 2.79 Å | Mutation | Yes | [51] |
| PDB Sequence |
AFTVTVPKDL
27 YVVEYGSNMT37 IECKFPVEKQ47 LDLAALIVYW57 EMEDKNIIQF67 VHGEEDLKTQ 77 HSSYRQRARL87 LKDQLSLGNA97 ALQITDVKLQ107 DAGVYRCMIS117 YGGADYKRIT 127 VKVNAPYAAA137 LEHHH
|
|||||
|
|
||||||
| 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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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 Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
|
|
|
Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
|
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
|---|---|---|---|
| Cell adhesion molecules | hsa04514 | Affiliated Target |
|
| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 2.19E-04 |
|---|---|---|---|---|---|
| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 5.36E-01 |
| Neighborhood connectivity | 2.66E+01 | Topological coefficient | 1.83E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
|---|---|
| Drug Property Profile of Target | Top | |
|---|---|---|
| (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 Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
|---|---|---|---|---|---|---|
| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
|---|---|---|---|---|---|---|
| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Cell adhesion molecules (CAMs) | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | PD-1 signaling | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Costimulation by the CD28 family | |||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | PD-1 as a potential target in cancer therapy. Cancer Med. 2013 October; 2(5): 662-673. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018 | |||||
| REF 5 | Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study.Breast Cancer Res Treat. 2018 Feb;167(3):671-686. | |||||
| REF 6 | Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.Lancet Oncol. 2018 Apr;19(4):521-536. | |||||
| REF 7 | 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. | |||||
| REF 8 | Sugemalimab: First Approval. Drugs. 2022 Apr;82(5):593-599. | |||||
| REF 9 | ClinicalTrials.gov (NCT04474119) KN046 in Subjects With Advanced Squamous Non-small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 10 | 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: 7990). | |||||
| REF 11 | ClinicalTrials.gov (NCT02409355) A Study of MPDL3280A Compared With Gemcitabine + Cisplatin or Carboplatin in Patients With Stage IV Squamous Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 12 | ClinicalTrials.gov (NCT03728556) A Study of CS1001 in Subjects With Stage III Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 13 | ClinicalTrials.gov (NCT05294172) KL-A167 Injection Combined With Cisplatin and Gemcitabine vs Placebo Combined With Cisplatin and Gemcitabine in the Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase III Clinical Trial. U.S.National Institutes of Health. | |||||
| REF 14 | 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: 7985). | |||||
| REF 15 | ClinicalTrials.gov (NCT02273375) Double Blind Placebo Controlled Controlled Study of Adjuvant MEDI4736 In Completely Resected NSCLC. U.S. National Institutes of Health. | |||||
| REF 16 | 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 17 | ClinicalTrials.gov (NCT04629339) Study of INCB086550 in Select Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 18 | ClinicalTrials.gov (NCT04560686) Bintrafusp Alfa Before Surgery for the Treatment of Untreated Resectable Non-small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 19 | ClinicalTrials.gov (NCT04891198) ENVAFOLIMAB Single-agent Treatment in Patients With Advanced Solid Tumors. 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 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 22 | 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: 7692). | |||||
| REF 23 | ClinicalTrials.gov (NCT01420965) Sipuleucel-T, CT-011, and Cyclophosphamide for Advanced Prostate Cancer. U.S. National Institutes of Health. | |||||
| REF 24 | Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013 Nov 20;31(33):4199-206. | |||||
| REF 25 | ClinicalTrials.gov (NCT03379259) Study of BGB-A333 Alone and in Combination With Tislelizumab in Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 26 | ClinicalTrials.gov (NCT04049617) Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in Participants With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 27 | ClinicalTrials.gov (NCT04442126) A Study of NM21-1480 in Adult Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 28 | ClinicalTrials.gov (NCT03922204) A Study of Bispecific Antibody MCLA-145 in Patients With Advanced or Metastatic Malignancies. U.S. National Institutes of Health. | |||||
| REF 29 | ClinicalTrials.gov (NCT02937844) Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme | |||||
| REF 30 | ClinicalTrials.gov (NCT04050709) QUILT 3.064: PD-L1 t-haNK In Subjects With Locally Advanced Or Metastatic Solid Cancers. U.S. National Institutes of Health. | |||||
| REF 31 | ClinicalTrials.gov (NCT04242147) A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of KD033 in Subjects With Metastatic or Locally Advanced Solid Tumors.. U.S. National Institutes of Health. | |||||
| REF 32 | ClinicalTrials.gov (NCT04786964) Study of Pemetrexed+Platinum Chemotherapy With or Without Cosibelimab (CK-301) in First Line Metastatic Non-squamous Non-Small Cell Lung Cancer (CONTERNO). U.S. National Institutes of Health. | |||||
| REF 33 | ClinicalTrials.gov (NCT02812875) A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas. U.S. National Institutes of Health. | |||||
| REF 34 | ClinicalTrials.gov (NCT03917381) GEN1046 Safety Trial in Patients With Malignant Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 35 | ClinicalTrials.gov (NCT04186637) An Open-label Study of ALPN-202 in Subjects With Advanced Malignancies (NEON-1). U.S. National Institutes of Health. | |||||
| REF 36 | Clinical pipeline report, company report or official report of Takeda. | |||||
| REF 37 | ClinicalTrials.gov (NCT03752177) A Study of LY3415244 in Participants With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 38 | 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 39 | ClinicalTrials.gov (NCT03809624) Study of INBRX-105 in Patients With Solid Tumors (PDL1x41BB). U.S. National Institutes of Health. | |||||
| REF 40 | Clinical pipeline report, company report or official report of Klus Pharma | |||||
| REF 41 | ClinicalTrials.gov (NCT04881045) A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTITUMOR ACTIVITY OF PF-07257876 IN PATIENTS WITH ADVANCED OR METASTATIC TUMORS. U.S.National Institutes of Health. | |||||
| REF 42 | ClinicalTrials.gov (NCT01455103) Phase 1 Biomarker Study of Anti-PDL-1 in Advanced Melanoma. U.S. National Institutes of Health. | |||||
| REF 43 | ClinicalTrials.gov (NCT03672305) Clinical Study on the Efficacy and Safety of c-Met/PD-L1 CAR-T Cell Injection in the Treatment of HCC | |||||
| REF 44 | 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 45 | Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol Res. 2015 Oct;3(10):1148-57. | |||||
| REF 46 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
| REF 47 | National Cancer Institute Drug Dictionary (drug id 740856). | |||||
| REF 48 | PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011 Jun;34(5):409-18. | |||||
| REF 49 | Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. | |||||
| REF 50 | Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016 May 24;7(21):30323-35. | |||||
| REF 51 | Fragment-based screening of programmed death ligand 1 (PD-L1). Bioorg Med Chem Lett. 2019 Mar 15;29(6):786-790. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.