A new database release (version 2022.2) of the IUPHAR/BPS Guide to Pharmacology was made on 9th June 2022. This blog post gives details of the key content updates and website changes. GtoPdb now contains:
- 3,002 human targets, 1,611 of which with curated quantitative ligand interactions.
- 11,348 ligands, 8,396 of which have curated quantitative target interactions.
- 1,756 approved drugs, 1,052 with curated quantitative interactions.
- Clinical use summaries for over 3,146 ligands of which 1,752 are approved drugs.
New targets and their interactions with newly curated ligands
Selectin E (OID 3200) and a selective antagonist uproleselan (LID 11995): Selectin E is a vascular adhesion molecule present on the endothelial cell surface that is involved in leukocyte migration and in cancer cell trafficking (especially metastasis). Uproleselan-mediated antagonism of selectin E binding is being investigated for anti-cancer potential and has been repositioned for anti-inflammatory action in patients with severe COVID-19 pneumonia (predicted to reduce leukocyte recruitment to the inflamed lungs).
Palmitoyl-protein thioesterase 1 (OID 3199) and the inhibitor ezurpimtrostat (LID 11991): Ezurpimtrostat (GNS561) is a small molecule inhibitor of palmitoyl-protein thioesterase 1 (PPT1). It induces lysosomal dysregulation which leads to inhibition of late-stage autophagy and cell death. Antitumour and antiviral activities have been demonstrated in vitro and in vivo. Anti-SARS-CoV-2 activity is being investigated in Phase 2 clinical trial NCT04637828.
CoV Non-structural protein 14 (nsp14 OID 3198) has been added as a separate entry in the Coronavirus (CoV) proteins family to allow effective curation of nsp14 inhibitors. The methyltransferase (MTase) activity of nsp14 is required for capping of the viral RNA transcript. Inhibition of this activity should disrupt viral replication. Two experimental inhibitors have been curated, TO507 (LID 11981) and compound 25 [PMID: 35439007] (LID 11971).
We have added those ligands from the DrugHunter ‘Molecules of the month’ sets for April and May that were absent from our curated ligands. Of the total April/May combined set of 18 compounds, we had already included 5 through our own curation efforts, and added 11 as new entries. We did not add branaplam (a RNA-targeted splicing modulator for spinal muscular atrophy and/or Huntington’s disease) as it doesn’t act via a defined protein target, and we didn’t add the HIV-1 protease inhibitor ‘compound 14’ as we currently don’t include HIV proteins as ligand/drug targets.
SARS-CoV-2/COVID-19 related ligands for coronavirus page- new and updates to existing entries
We reviewed the compounds in current COVID-19 clinical trials (from clinicaltrials.gov) to identify agents (particularly small molecule compounds) that either didn’t exist in the GtoPdb or which needed updated curation wrt clinical potential as antivirals or treatments for symptomatic COVID-19. The results include:
- acebilustat (CTX-4430)
- apabetalone (RVX 208)
- compound 25 [PMID: 35439007]
- danicopan (ACH-4471)
- dapansutrile (OLT1177)
- ezurpimtrostat (GNS561)
- isuzinaxib (APX-115)
- uproleselan (GMI-1271)
- zapnometinib (ATR-002)
New FDA drug approvals
In May, the FDA approved 3 drugs that are ‘first-in-class’ therapeutics. In date order of approval these are:
- Vonoprazan (LID 11549) is the first potassium competitive acid blocker (PCAB) class drug to be FDA approved. Its interaction with the gastric proton pump (H+,K+-ATPase) is reversible, so it offers advantages over the existing irreversible proton pump inhibitors (PPIs). Tegoprazan and revaprazan are two additional PCABs that are authorised for clinical use in South Korea.
- Tapinarof is the first aryl hydrocarbon receptor (AhR) agonist to enter clinical use. It is indicated for the treatment of psoriasis, and provides a number of advantages compared to standard corticosteroid treatments, particularly in respect of side-effects and long-term use.
- Tirzepatide is the first in its class of dual acting glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonists (‘twincretin’). The FDA approved it for T2DM management. Recently published Phase 3 results from the SURMOUNT-1 study (NCT04184622) demonstrate that this dual agonist approach also produces significant and sustained weight reduction in obese patients [PMID:35658024].