Page 112 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences PI3K-α inhibitors for cancer immunotherapy

1. Introduction the four isotypes of p110: alpha, beta, gamma, and delta,
respectively. These p110 isotypes activate downstream
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Human physiology is governed by intricate cellular signaling pathways, including binding corresponding
metabolisms, which exemplify how cell-specific programs ligands to tyrosine kinase receptors (RKTs). However, the
9
efficiently regulate overall health and well-being. The body p110-alpha isotype is involved in insulin-like signaling,
initiates cascade mechanisms of cellular signaling pathways p110-beta plays a role in platelet-derived aggregation,
to control physiological functions such as cell proliferation, thrombosis, and insulin signaling, while p110-gamma and
growth, survival, differentiation, and metabolism. Cells p110-delta isotypes are expressed in lymphocyte activation,
1
serve as the building blocks of life; however, genetic mast cell degranulation, and chemotaxis. Furthermore,
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mutations or alterations can lead to anomalies, disrupting the catalytic p110 subunit forms a complex with one of
the mitotic and cytokinetic regulatory mechanisms of the three p85-related regulatory subunits: p85-alpha, p85-
the cells. Over time, dysregulation of cellular signaling beta, and p55-gamma, encoded by the genes PIK3R1,
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progresses to carcinogenic effects, affecting various PIK3R2, and PIK3R3, respectively. 14,16,17 Activation of the
enzyme functions, such as phosphoinositide 3-kinase p85 regulatory subunit occurs through the stimulation
alpha (PI3K-α), an isoform of the phosphatidylinositol-3- of the receptor tyrosine kinase, where it binds to
kinase (PI3K) family of enzymes. phosphotyrosine residues in the receptor tyrosine kinase.

PI3Ks are lipid kinases responsible for phosphorylating Such a process unleashes the p110 catalytic subunit from
the -OH moiety at the 3’ position of the inositol ring, inhibition of the p85 regulatory subunit. Progressively,
3
generating phosphatidylinositol-3,4,5-triphosphate PI3K localizes to the cellular membrane, where the p110
(PIP3). They play a central role in regulating cell cycle, subunit converts phosphatidylinositol 4,5-biphosphate
2,3
apoptosis, DNA repair, cellular senescence, angiogenesis, (PIP2) into PIP3, a lipid secondary messenger, which then
cellular metabolism, and motility. Besides, they serve as activates the downstream effector protein kinase B (also
intermediate signaling molecules that are well known for known as AKT), promoting its translocation to the inner
their roles in the PI3K/serine-threonine protein kinase membrane of cells, where it is phosphorylated and activated
(AKT)/mammalian target of rapamycin (mTOR) (PI3K/ by phosphoinositide-dependent protein kinase (PDK)-1,
AKT/mTOR) signaling pathway. 2,4-6 Furthermore, the PDK2, and mTor-rictor. AKT, a serine/threonine kinase,
3,5
PI3K/AKT/mTOR pathway is involved in oncogenesis together with mammalian target of rapamycin complex 1
and tumorigenesis, 5,7,8 which is frequently dysregulated (mTORC1), further modulates the activities of downstream
in human cancers, such as pancreatic cancer, breast biomacromolecules, such as B-cell lymphoma-2 (BCL-2),
2
5
6
cancer, colorectal, and ovarian cancer. At the molecular BCL-2 antagonist of cell death (BAD), forkhead box O
level, alterations at numerous nodes are described in (FOXO), p53, p27, transcription factor, tuberous sclerosis
different tumor types, including activating mutations complex 2 (TSC2), glycogen synthase kinase-3β (GSK3β),
and/or the amplification of phosphatidylinositol-4,5- insulin-like growth factors, cyclin D1, C-MYC (cellular
biphosphate 3-kinase catalytic subunit alpha (PIK3CA), myelocytomatosis) oncogene, nuclear factor kappa B (NF-
mutation or overexpression of upstream receptor tyrosine κB), caspase-3 and caspase-9, and murine double minute 2
kinases (RTKs), or inactivating mutations or deletions (MDM2) (Figure 1). These biomacromolecules regulate
3,5
of phosphatase and tensin homolog (PTEN) from protein synthesis, cell survival, cell cycle progression,
chromosome 10. 4,7 cellular growth, proliferation, motility transformation,

In the recent decade, several studies have described DNA repair, glucose metabolism, and drug resistance. 3,18,19
the role of the PI3K pathway, 2-5,9,10 which is a complex PI3K classes II and III also play significant roles in cell-
cascade of signal transduction that regulates proliferation, specific functions and metabolism. There are three isoforms
growth, differentiation, protein synthesis, glucose of PI3K class II, including PI3KC2-alpha, PI3KC2-beta,
metabolism, migration, apoptosis, and other intracellular and PI3KC2-gamma. These isoforms of PI3K class II are
3-5
metabolisms activated in diverse types of cancer. In monomers with a high molecular weight. 16,20 Moreover,
3,9
humans, PI3K exists in three classes – Classes I, II, and class II monomers have no regulatory subunits but
3,5
III, and is enzymes with a molecular weight of about possess individual catalytic moieties that interact directly
3,4
200 – 300 kDa. Class I of the PI3K subfamily is primarily with phosphorylated adapter proteins. 16,20 In contrast
4
linked to oncogenesis. 4,11-13 The PI3K is a heterodimer to PI3KC2-beta, PI3KC2-alpha appears to be involved
comprised both the catalytic and regulatory subunits. in cell migration and neuronal cell survival, as well as
The phosphorylation of the regulatory subunit leads to clathrin-mediated vesicle trafficking, insulin signaling,
the activation of p110, the catalytic subunit of PI3K. The neurosecretory granular exocytosis, and smooth muscle
genes PIK3CA, PIK3CB, PIK3CG, and PIK3CD encode contraction. On the other hand, the role of PI3KC2 is
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Volume 7 Issue 2 (2024) 2 doi: 10.36922/itps.2340