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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2D Structure
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Physico-chemical Properties
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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
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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
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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