Page 113 - ITPS-7-2

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

Figure 1. PI3K/AKT/mTOR signaling pathway in human cancer. Exposure of cells to DNA damage reduces intracellular proportions of MDM2, which
enables p53 accumulation and stabilization, leading to the initiation of DNA repair pathways. 5
Abbreviations: BAX: BCL-2-associated X protein; BIM: BCL-2-interacting mediator of cell death; INPP4B: Inositol polyphosphate-4-phosphatase type II
B; MDR1: Multidrug resistance protein 1; Myt1: Myt1 kinase; S6K: Ribosomal protein S6 kinase; Wee 1: Wee 1 kinase; XIAP: X-linked inhibitor of
apoptosis protein; 4EBP1: Eukaryotic translation initiation factor 4E-binding protein 1.

not established. The PI3KC3 gene produces the class III frequently up-regulated isoform of PI3K in human cancer,
PI3K, also known as vacuolar protein sorting 34, which effectively blocks PI3K/AKT/mTOR signaling in response
is a potential serine/threonine protein tyrosine kinase to diverse growth stimuli. Consequently, PI3K-α has
25
regulatory subunit. Vacuolar protein sorting 34 is also emerged as a key target that is primarily affected by cancer
linked to mTOR signaling and plays a part in the vesicular mutations, gene rearrangement, and gene amplification,
15
transport of membrane proteins to the lysosome. making it an attractive focus for drug development. 23,26
Furthermore, the PI3K/AKT/mTOR pathway plays a Ongoing efforts aim to exploit and develop novel selective
critical role in the pathogenesis and provides survival inhibitors for PI3K-α as a promising drug target for anti-
advantages in hematologic malignancies such as leukemia, inflammation and anti-cancer therapy. Moreover, several
lymphoma, and myeloma. 3 kinase inhibitors for PI3K-α have been discovered and
PI3K-α is a member of the Class 1A PI3K family of synthesized to regulate the proliferation of cancer cells.
enzymes and is activated by various upstream signaling These small-molecule drugs exhibit unique potency.
biomacromolecules, such as growth factor receptors, Notable examples include buparlisib (BKM120), pilaralisib
which phosphorylate phosphatidylinositols in the cell (XL147), pictilisib (GDC-0941), alpelisib (BYL719),
27
membrane. It is linked to several tumorigeneses through umbralisib, and taselisib (GCD-0032), serving as
28
4,24
amplification, overexpression, and mutation of the PI3K isoform inhibitors utilized in the treatment of
PIK3CA gene, following the PI3K/AKT/mTOR pathway. pancreatic cancer, breast cancer, 2,5,29 or ovarian cancer.
21
2
6
In addition, PI3K-α specifically consists of heterodimers of Despite their development, most inhibitors encountered
a p110-α catalytic subunit and a p85 regulatory subunit. challenges in clinical trials, displaying poor efficacies
22
The PI3K-α isoform transmits various extracellular stimuli due to nanotherapeutic-associated toxicity resulting
through signaling pathways that regulate numerous from on-target and off-target effects. 21,24 To maximize
cellular processes, including cell proliferation, motility, cell effectiveness and minimize negative side effects, medicinal
death, and cell invasion, thereby playing a crucial role in chemists focus on identifying isoform-selective PI3K-α
the physiology of cells. 23,24 inhibitors. This discovery of isoform-selective PI3K-α
21
Recently, it has been demonstrated that selective inhibitors remains a priority to engineer therapeutic
inactivation of the PI3K-α isoform, which is the most drugs with enhanced efficacy and reduced side effects
21
Volume 7 Issue 2 (2024) 3 doi: 10.36922/itps.2340