| Structural highlights
Function
[PK3CD_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The predominant expression of phosphoinositide 3-kinase delta (PI3Kdelta) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kdelta should avoid potential side effects associated with the ubiquitously expressed PI3Kalpha and beta isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kdelta selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kdelta and PI3Kgammadelta-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjogren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kdelta.
Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.,Hoegenauer K, Soldermann N, Zecri F, Strang RS, Graveleau N, Wolf RM, Cooke NG, Smith AB, Hollingworth GJ, Blanz J, Gutmann S, Rummel G, Littlewood-Evans A, Burkhart C ACS Med Chem Lett. 2017 Aug 25;8(9):975-980. doi: 10.1021/acsmedchemlett.7b00293., eCollection 2017 Sep 14. PMID:28947947[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002 Aug 9;297(5583):1031-4. Epub 2002 Jul 18. PMID:12130661 doi:http://dx.doi.org/10.1126/science.1073560
- ↑ Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002 Sep 16;196(6):753-63. PMID:12235209
- ↑ Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 2004 Oct 21;431(7011):1007-11. PMID:15496927 doi:http://dx.doi.org/10.1038/nature02991
- ↑ Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol. 2005 Sep 1;175(5):2783-7. PMID:16116162
- ↑ Jarmin SJ, David R, Ma L, Chai JG, Dewchand H, Takesono A, Ridley AJ, Okkenhaug K, Marelli-Berg FM. T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J Clin Invest. 2008 Mar;118(3):1154-64. doi: 10.1172/JCI33267. PMID:18259608 doi:http://dx.doi.org/10.1172/JCI33267
- ↑ Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med. 2008 Sep 29;205(10):2419-35. doi: 10.1084/jem.20072327. Epub 2008 Sep , 22. PMID:18809712 doi:http://dx.doi.org/10.1084/jem.20072327
- ↑ Saudemont A, Garcon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K, Colucci F. p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5795-800. doi:, 10.1073/pnas.0808594106. Epub 2009 Mar 18. PMID:19297623 doi:http://dx.doi.org/10.1073/pnas.0808594106
- ↑ Hoegenauer K, Soldermann N, Zecri F, Strang RS, Graveleau N, Wolf RM, Cooke NG, Smith AB, Hollingworth GJ, Blanz J, Gutmann S, Rummel G, Littlewood-Evans A, Burkhart C. Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors. ACS Med Chem Lett. 2017 Aug 25;8(9):975-980. doi: 10.1021/acsmedchemlett.7b00293., eCollection 2017 Sep 14. PMID:28947947 doi:http://dx.doi.org/10.1021/acsmedchemlett.7b00293
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