P110δ#Pharmacology

{{Short description|Protein-coding gene in the species Homo sapiens}}

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.

p110δ regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzyme is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ is a promising target for drugs that aim to prevent or treat inflammation, autoimmunity and transplant rejection.

Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. The class I PI3Ks display a broad phosphoinositide lipid substrate specificity and include p110α, p110β and p110γ. p110α and p110β interact with SH2/SH3-domain-containing p85 adaptor proteins and with GTP-bound Ras.

Biochemistry

Like the other class IA PI3Ks, p110δ is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated p85α, p55α, p50α or p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. There is no evidence for selective association between p110α, p110β or p110δ for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins that have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ to the plasma membrane where its substrate PtdIns(4,5)P2 is found. The conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as Akt), Tec family kinases and other proteins that contain PH domains. In immune cells, antigen receptors, cytokine receptors and costimulatory and accessory receptors stimulate tyrosine kinase activity and hence all have the potential to initiate PI3K signalling.

Functions

For reasons that are not well understood, p110δ appears to be activated in preference to p110α and p110β in a number of immune cells. The following is a brief summary of the role of p110δ in selected leukocyte subsets.

= T cells =

In T cells, the antigen receptor (TCR) and costimulatory receptors (CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. T cell specific deletion of p110δ has revealed its role in antibody responses.

This may in part result from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt in that absence of p110δ activity.

= B cells =

p110δ is a regulator of B cell proliferation and function. p110δ-deficient mice have deficient antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum) and marginal zone B cells, found in the periphery of spleen follicles).

= Mast cells =

p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.

= Neutrophils =

In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils.

= Dendritic cells =

p110δ controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses in dendritic cells and mice carrying an inactive p110δ is susceptible to lipopolysaccharide mediated endotoxin shock.{{cite journal | vauthors = Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno IM, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B | display-authors = 6 | title = The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock | journal = Nature Immunology | volume = 13 | issue = 11 | pages = 1045–1054 | date = November 2012 | pmid = 23023391 | pmc = 4018573 | doi = 10.1038/ni.2426 }}

Activated PI3K delta syndrome

Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI. {{cite journal | vauthors = Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S | display-authors = 6 | title = Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage | journal = Science | volume = 342 | issue = 6160 | pages = 866–71 | date = November 2013 | pmid = 24136356 | doi = 10.1126/science.1243292 | pmc = 3930011 | bibcode = 2013Sci...342..866A }}{{cite journal | vauthors = Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G | display-authors = 6 | title = Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency | journal = Nature Immunology | volume = 15 | issue = 1 | pages = 88–97 | date = January 2014 | pmid = 24165795 | doi = 10.1038/ni.2771 | pmc = 4209962 }}

Pharmacology

US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114.{{cite journal | vauthors = Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE | title = Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement | journal = Journal of Immunology | volume = 170 | issue = 5 | pages = 2647–54 | date = March 2003 | pmid = 12594293 | doi = 10.4049/jimmunol.170.5.2647 | doi-access = free }} This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.{{cite journal | vauthors = Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD | title = Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model | journal = FASEB Journal | volume = 20 | issue = 3 | pages = 455–65 | date = March 2006 | pmid = 16507763 | doi = 10.1096/fj.05-5045com | doi-access = free | s2cid = 8013052 }}

The p110δ inhibitor idelalisib was developed by Gilead Sciences.{{cite journal | vauthors = Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, Younes A, Lannutti BJ | title = PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma | journal = Blood | volume = 119 | issue = 8 | pages = 1897–900 | date = February 2012 | pmid = 22210877 | doi = 10.1182/blood-2011-10-386763 | doi-access = free }} Idelalisib in combination with rituximab showed favourable progression free survival in a phase III clinical trial for chronic lymphocytic leukemia (CLL) compared with patients that received rituximab and placebo.{{cite journal | vauthors = Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM | display-authors = 6 | title = Idelalisib and rituximab in relapsed chronic lymphocytic leukemia | journal = The New England Journal of Medicine | volume = 370 | issue = 11 | pages = 997–1007 | date = March 2014 | pmid = 24450857 | pmc = 4161365 | doi = 10.1056/NEJMoa1315226 }}

In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.[https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm FDA approves Zydelig for three types of blood cancers]

In September 2017 copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.{{cite web | url = https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm | title = FDA approves new treatment for adults with relapsed follicular lymphoma | date = September 14, 2017 | publisher = US Food and Drug Administration}}

In September 2018 duvelisib was approved by the FDA as a treatment for relapsed or refractory CLL, and relapsed follicular lymphoma (FL) patients, who have received at least two prior therapies.{{cite web|title=Full prescribing information: COPIKTRA (duvelisib)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf|website=U.S. Food and Drug Administration|access-date=23 October 2018}}

A 2015 study found that p110δ inhibitors had a side-effect of boosting mouse immune responses against multiple cancers, including both solid and hematological types. Breast cancer mice survival times nearly doubled and spread significantly less, with far fewer and smaller tumors. Post-surgical survival also improved. Subject immune systems could also develop an effective memory response, extending protection.{{Cite web|title = Leukemia drug found to stimulate immunity against many cancer types {{!}} KurzweilAI|url = http://www.kurzweilai.net/leukemia-drug-found-to-stimulate-immunity-against-many-cancer-types|website = www.kurzweilai.net|access-date = 2016-01-01|date = June 17, 2014}}

Interactions

PIK3CD interacts with PIK3R1, and PIK3R2.

References

{{Reflist|30em|refs =

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{{cite journal | vauthors = Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, Vanhaesebroeck B, Turner M, Webb L, Wymann MP, Hirsch E, Ruckle T, Camps M, Rommel C, Jackson SP, Chilvers ER, Stephens LR, Hawkins PT | display-authors = 6 | title = Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils | journal = Blood | volume = 106 | issue = 4 | pages = 1432–40 | date = August 2005 | pmid = 15878979 | doi = 10.1182/blood-2005-03-0944 | doi-access = free }}

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