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Page 12 of 25 Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105

cell free assays, GDC-0980 treatment results in the inhibition of class 1 PI3K isoforms α, β, δ and γ at low
nanomolar IC values of 5, 27, 7 and 14 nmol/L, respectively and mTOR inhibition with Ki value of 17 nmol/L.
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These preclinical data show high potency and selectivity of GDC-0980 inhibitory activity. However, GDC-
[72]
0980 has less effectiveness than everolimus in metastatic renal cell carcinoma .
NVP-BGT226, a potent orally bioavailable dual inhibitor of PI3K and mTOR signaling pathways, blocks
cell cycle at G0/G1 phase and induces autophagy and apoptosis. It is shown that NVP-BGT226 suppresses
the growth of primary myeloma and common myeloma cell lines at nanomolar concentrations. Specifically,
NVP-BGT226 inhibits PI3Kα, β and γ isoforms with IC values of 4, 63 and 38 nmol/L, respectively. The
50
analysis of NVP-BGT226 effects in hepatocellular carcinoma (HCC) shows cell growth and proliferation
inhibition with potent cytotoxic activity. Hence, the capabilities of NVP-BGT226 in targeting PI3K and
[73]
mTOR may represent it as an anticancer agent in HCC . NVP-BEZ235, an imidazo[4,5-c]quinoline
derivative, is a dual kinase inhibitor of PI3K and mTOR that binds to the ATP binding site and halts cell
cycle at G1 phase. When the compound is given orally to animal models, it displayed disease stasis of human
[74]
cancers . Although co-crystallization studies of this compound with targets are ongoing, docking studies
revealed that NVP-BEZ235 forms H-bond with ATP binding cleft residues including Val851, Asp933, and
Ser774 of PI3Kα homology model. This compound has entered phase1 clinical trials for the treatment of
breast cancer, advanced solid tumors and cowden syndrome.

Unc-51-like kinases inhibitors
[34]
ULK belong to serine/threonine kinase family proteins, and play a crucial role in autophagy regulation .
Humans contain four ULK kinases including ULK1, ULK2, ULK3 and ULK4. Among them, ULK1 is well
studied and it is utmost important for autophagy initiation. Under nutrient deprivation, ULK1 is activated by
several up-stream signals (e.g., AMPK, etc.) and then initiates autophagy process by recruiting various other
proteins (i.e., FIP200, ATG101 and ATG13 for ULK complex) to the on-site of autophagy initiation. Thus,
ULK1 and its associated proteins (i.e., ULK complex) play essential roles in cell survival mechanism under
[75]
nutrient deficiency . However, disruption of ULK1 and its associated protein complex lead to autophagy
inhibition and cell death. As cancer cells generate energy and nutrients through autophagy mechanism and
eventually help in cell survival and tumor progression, disruption of ULK1 function by developing small
molecule inhibitors has become an attractive approach to treat cancer [75,76] . As a proof of concept, few ULK1
inhibitors have been reported in the literature [Figure 9].

MRT67307 and MRT68921 are two closely related derivatives with different substitution pattern on the
pyrimidine ring. MRT67307 inhibits ULK1 and ULK2 with an IC of 45 and 38 nmol/L, respectively. This
50
compound led to the identification of MRT68921, that has 15-fold improved inhibition of ULK1 (IC = 2.9
50
nmol/L) and 30-fold improved inhibition of ULK2 (IC = 1.1 nmol/L), when compared with MRT67307.
50
Studies using MRT67307 and MRT68921 in MEFs cells show that these compounds are able to block
autophagic flux. In addition, MRT68921 treated cells show significant increase in SQSTM1 level and decrease
in LC3-2/LC3-1 ratio. These results suggested that MRT68921 treatment efficiently inhibits ULK-mediated
[77]
autophagy . However, the molecular basis of this block remains to be elucidated. SBI-0206965 is a potent
and specific inhibitor of ULK1 with an IC of 108 nmol/L and also selectively inhibits ULK2 with IC of
50
50
711 nmol/L, but with less efficacy when compared with ULK1. Inhibition of ULK1 in NSCLC cells results
[51]
in anti-proliferative effect . Specifically, SBI-0206965 suppresses phosphorylation events in cells that are
mediated by ULK1. SBI-0206965 at 10 µmol/L concentration shows high selectivity and inhibits only 10 out
of 456 kinases.

[75]
In 2015, Lazarus et al. reported the first crystal structure of ULK1 in complex with multiple inhibitors. The
structure consists of an N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting
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domain. They used a standard P-ATP radioactive assay to screen a collection of 746 compounds against
ULK1 that led to the identification of several pyrazole aminoquinazolines as ULK1 inhibitors. For example,