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Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105 Page 9 of 25

Figure 6. Pan-PI3K inhibitors

[56]
under normal as well as starvation conditions . Surprisingly, prolonged treatment (upto 9h) with 3-MA has
[59]
shown autophagy flux promotion by increasing the autophagic markers levels such as LC3 protein .
Wortmannin, a fungal metabolite is a selective, irreversible and potent inhibitor of PI3K that inhibits
autophagic sequestration. It has been demonstrated that the lower concentration (nanomolar) of wortmannin
potently and specifically inhibits PI3K; whereas, higher concentrations can inhibit the ataxia telangiectasia
gene-related DNA-dependent protein kinase. At physiological pH (6-8.5), wortmannin compete with ATP
and ATP analogs binds to PI3K, this suggests that wortmannin binds in the substrate binding site of PI3K.
More importantly, site directed mutagenesis studies shows that Lys802 is essential to form nucleophilic
[60]
interaction . These observations of wortmannin interactions with PI3K provide the molecular basis for
designing better inhibitors for PI3K kinase family proteins to treat cancer via autophagy inhibition.

Ly294002, an inhibitor of PI3K class family proteins is derived from the flavonoid quercetin. Ly294002 is
not completely selective for PI3K family proteins, and additionally act on other unrelated proteins and lipid
kinases . Ly294002 binds at the ATP binding site and is more stable in solution than wortmannin. More
[61]
importantly, this compound shows its inhibitory effect with IC values of 0.5, 0.97 and 0.7 µmol/L for PI3Kα,
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β and δ targets, respectively [61,62] . To improve the selectivity and specificity, many Ly294002 analog were
synthesized; SF1126 a prodrug of Ly294002 entered into clinical trial but was recently halted.

CLR457, a potential inhibitor of all PI3K isoforms is an orally bioavailable inhibitor with antineoplastic
activity. It has been extensively characterized by in vitro biochemical methods and in vivo tumor xenograft
[63]
studies . Dose limiting toxicity studies show that CLR457 potently inhibited PI3K isoforms including
p110α (IC = 89 nmol/L), p110β (IC = 56 nmol/L), p110δ (IC = 39 nmol/L) and p110γ (IC = 230 nmol/L).
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However, the characteristics such as poor tolerability and limited antitumor activity of CLR457 resulted in
the termination of clinical development.
Recently, omipalisib (GSK2126458) is presented as an autophagy inhibitor that specifically binds to PI3K in
PI3K/mTOR signaling pathway. It directly targets Akt phosphorylation by PI3K and reverse phosphorylation
of Akt by mTOR. It is an orally bioavailable dual ATP-competitive inhibitor of PI3K and mTOR with high
[64]
potency . The indirect inhibition of Akt by omipalisib induces cytotoxicity and promotes autophagic
cell death at 0.5 μmol/L dose. Further, investigations carried out to know whether the mechanism of cell
death occurs through autophagy or apoptosis reported that there is no significant difference in treated and
untreated cells when apoptosis markers were used . Cell culture studies reported that GSK2126458 arrests
[65]
cell cycle at G1 phase and affects proliferation of several cell lines such as breast cancer cell lines T47D
and BT474 with IC values of 3 and 2.4 nmol/L, respectively. Currently, omipalisib is in clinical trials for
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idiopathic pulmonary fibrosis and solid tumors. The difficulties in PI3K inhibitors such as lower solubility of
wortmannin and broad spectrum inhibition of Ly294002 and limited antitumor activity of CLR457, further
necessitate the identification of new inhibitors for PI3K.