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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 11 of 25

Figure 8. Dual PI3K/mTOR inhibitors

apoptosis by activation of caspase cascade. Autophagy inhibition by shRNA and autophagy inhibitors such
as bafilomycin A1 and 3-MA, notably sensitized WYE-354 mediated anti-colon cancer cell activity. In
vivo studies, further witnessed that WYE-354 administration in severe combined immunodeficient mice
[69]
inhibited growth of xenografts . PP30 is an adenine-mimetic pyrazolopyrimidine scaffold compound that
selectively inhibits mTORC1 (IC = 8 nmol/L) and mTORC2 (IC = 80 nmol/L).
50
50
PI3K/mTOR inhibitors
mTOR shares high sequence homology with the hinge region of PI3K, as they belong to the same family of
phosphatidylinositol 3-kinase. Hence, several small molecules target both mTOR and PI3K simultaneously.
PI-103 [Figure 8] belongs to pyridofuropyrimidine class of compounds and is a multi-target inhibitor that
inhibits PI3K and mTOR. Studies using human leukemia cell lines including MV4-11, OCI-AML3 and
MOLM14 clearly indicated that PI-103 treatment arrested the cell cycle at G1 phase and eventually reduced
the cell proliferation in these cells. The effects of PI-103 in AML patient samples have shown that 82%
reduction of AML progenitor clonogenecity. The significant increase in apoptosis is also observed in blast
cells when treated with 1.0 µmol/L of PI-103. On the other hand, PI3K/Akt and mTOR inhibition has also
been shown when the AML blast cells treated with RAD001 and IC87114 (RAD + IC); but the mechanism of
antiproliferative effect is yet to be elucidated. At the same time, this study also reported that inhibitory effect
[70]
of PI-103 is not much higher than that of RAD + IC in AML blast cells .

PKI-587, a dual ATP competitive inhibitor of known therapeutic targets PI3K (PI3K-α and PI3K-γ) and
[56]
mTOR is an orally bioavailable inhibitor . It shows potent inhibitory efficacies of PI3K-α, PI3K-γ and
mTOR with IC values of 0.4, 5.4 and 1.6 nmol/L, respectively. PKI-587 not only inhibits wild type PI3K, but
50
also exhibits inhibitory activity against most commonly occurring mutants including H1047R and E545K of
PI3K with an IC value of 0.6 nmol/L for both forms. In in vitro, PKI-587 has exhibited excellent antitumor
50
[71]
activity in over 50 human cancer cell lines . In in vivo, PIK-587 showed inhibition of tumor growth in
MDA-MB-261, BT474, HCT116, H1975 and U87MG xenograft models, when administrated intravenously.

A novel inhibitor apitolisib, also known as RG7422/GDC-0980 is an orally available dual PI3K and mTOR
inhibitor with excellent pharmaceutical and pharmacokinetics properties. The GDC-0980 inhibition of PI3K
and mTOR overexpression has shown significant reduction in tumor cell growth by inducing apoptosis. In