leniolisib   Click here for help

GtoPdb Ligand ID: 9424

Synonyms: CDZ-173 | CDZ173 | Example 67 [WO2012004299] | Joenja®
Approved drug PDB Ligand Immunopharmacology Ligand
leniolisib is an approved drug (FDA (2023))
Compound class: Synthetic organic
Comment: Leniolisib (CDZ173) is an orally bioavailable, potent phosphatidylinositol 3-kinase inhibitor (PI3K) inhibitor, with selectivity for the PI3Kδ isoform [3]. Novartis originally developed CDZ173 as a treatment for autoimmune diseases, but has rapidly repurposed it for its potential in patients with Activated PI3K Delta Syndrome (APDS, a.k.a. p110 delta activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency, or PASLI). APDS is an ultra-rare genetic immunodeficiency disease characterised by lymphoproliferation, recurrent infections from childhood, and an increased risk of EBV-associated lymphoma. APDS is known to be caused by autosomal dominant, gain-of-function mutations in the PIK3CD gene which encodes the PI3Kδ protein [4,7].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 7
Topological polar surface area 83.48
Molecular weight 450.2
XLogP 2.47
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CCC(=O)N1CCC(C1)Nc1ncnc2c1CN(CC2)c1cnc(c(c1)C(F)(F)F)OC
Isomeric SMILES CCC(=O)N1CC[C@@H](C1)Nc1ncnc2c1CN(CC2)c1cnc(c(c1)C(F)(F)F)OC
InChI InChI=1S/C21H25F3N6O2/c1-3-18(31)30-6-4-13(10-30)28-19-15-11-29(7-5-17(15)26-12-27-19)14-8-16(21(22,23)24)20(32-2)25-9-14/h8-9,12-13H,3-7,10-11H2,1-2H3,(H,26,27,28)/t13-/m0/s1
InChI Key MWKYMZXCGYXLPL-ZDUSSCGKSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
Leniolisib (CDZ173) was evaluated in clinical trial in patients with genetically activated PI3Kδ (i.e. patients with APDS/PASLI; see Phase 2/3 trial NCT02435173). Positive results from NCT02435173 are reported by Rao et al. (2017) [6], showing that leniolisib was well tolerated and improved laboratory and clinical parameters in APDS patients. The FDA approved leniolisib as a treatment for APDS in March 2023 [2].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Gain-of-function mutations in PI3Kδ causes hyperactivation of mTOR signaling, which in turn skews the differentiation of CD8+ T cells to short-lived effector cells and severely impairs development of functional memory T cells and B cells. Inhibition of aberrant PI3Kδ activity is predicted to restore T cell differentiation and T and B cell function.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02435173 Study of Efficacy of CDZ173 in Patients With APDS/PASLI Phase 2/Phase 3 Interventional Novartis Compared to placebo, leniolisib therapy reduced lymphadenopathy and increased the percentage of naïve B cells in patients with APDS, which together demonstrate a beneficial modulation of the immune dysregulation/deficiency that are associated with APDS. 5