CHAPT ER

12
mTOR Inhibitors in Oncology
Jeroen Verheijen, Ker Yu and Arie Zask

Contents

1. Introduction
2. Mechanism of mTOR Inhibition
2.1 Inhibition of mTORC1
2.2 Inhibition of mTORC1 and mTORC2
3. Rapamycin Analogs in the Clinic
3.1 Temsirolimus (CCI-779, Torisels)
3.2 Everolimus (RAD001)
3.3 Deforolimus (AP23573, MK-8669)
4. Pre-Clinical Rapamycin Analogs
5. ATP Competitive mTOR Inhibitors
5.1 Mixed mTOR/PI3K inhibitors
5.2 Selective mTOR inhibitors
6. Other mTOR Inhibitors
7. Conclusion
References

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1. INTRODUCTION
The mammalian target of rapamycin (mTOR) is the founding member of a family
of unconventional high molecular weight serine/threonine protein kinases
termed phosphoinositide-3-kinase (PI3K)-related kinases (PIKKs) (reviewed in
[1]). PIKKs play diverse roles in cell growth and surveillance of both the genome
and transcriptome. The catalytic sites of the PIKK family resemble those of PI3K
but differ from those of the broad-spectrum conventional protein kinases. These
distinctive structural features coupled with the essential biological function and
scarcity of PIKKs in the entire human kinome of approximately 500 kinases
Wyeth Research, Pearl River, New York 10965
Annual Reports in Medicinal Chemistry, Volume 43
ISSN 0065-7743, DOI 10.1016/S0065-7743(08)00012-2

r 2008 Elsevier Inc.

All rights reserved.

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highlight mTOR and the PIKK family as exciting drug targets for the
development of potent and selective inhibitor therapy.
Molecular and biochemical characterization of mTOR uncovered an important signaling network that regulates fundamental aspects of cell growth,
metabolism, and proliferation in response to growth factors, nutrients, and
energy supply (reviewed in [2,3]). In human cells, mTOR primarily resides in
two functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2
(mTORC2), which are differentially formed through complex-specific binding
partners, and are believed to dictate subcellular mTOR functions and/or
substrate specificity. mTORC1 is composed of mTOR, Raptor, mLST8/GbL, and
PRAS40, while mTORC2 contains mTOR, Rictor, mLST8/GbL, and mSIN1. A
dominant role in promoting cellular translation is well established for mTORC1
through its direct phosphorylation of the ribosomal protein S6 kinase 1 (S6K1)
and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Both
S6K1 and 4E-BP1 are regulatory proteins in translation machinery and cell
growth. The recent discovery of mTORC2 has elucidated new aspects of mTOR in
cancer biology. mTORC2 phosphorylates the serine/threonine kinase AKT,
leading to an increased cell survival and resistance to chemotherapy. mTORC2 is
also predicted to modulate the cytoskeletal network in human cells through
biochemical mechanisms yet to be identified. These mTORC2-related functions
are vital to the maintenance and progression of malignant and metastatic cancer
cells [2,3].
Although the mTOR gene locus is not known to be mutated or amplified
in cancer, mTOR signaling contributes to tumorigenic effects by numerous
oncogenic proteins such as PI3K, AKT, EGFR, HER2/neu, and BCR-Abl as well
as the effects due to loss of tumor-suppressor genes such as the phosphatase and
tensin homolog (PTEN), tuberous sclerosis complex (TSC), von Hippel-Lindau
(VHL), and neurofibromatosis type I (NF1) (reviewed in [4,5]). In preclinical
models of these diseases, inhibition of mTOR signaling often correlates with
anti-tumor activity. Heightened mTOR activity, as indicated by an elevated
phosphorylation of its downstream substrates phospho-S6K1, phospho-S6, and
phospho-AKT, has frequently been observed in clinical samples of various solid
tumors as well as hematopoietic malignancies. There is strong preclinical and
some clinical evidence that certain tumors with deregulated PI3K/AKT/mTOR
signaling are particularly susceptible to mTOR inhibition (reviewed in [6]).

2. MECHANISM OF mTOR INHIBITION

2.1 Inhibition of mTORC1
Rapamycin (1), at single digit nanomolar concentrations, forms a tight complex
with the 12 kDa FK506-binding protein (FKBP12) that in turn binds with high
affinity to the FKBP12-rapamycin-binding domain (FRB domain) adjacent to the
catalytic domain of mTOR (Figure 1) [79]. The resulting ternary complex may
alter the composition and/or conformation of mTORC1, thereby interfering with

mTOR Inhibitors in Oncology

HEAT REPEATS

FAT

FRB

FKBP12

kinase
kinase

191

FATC
mTOR (290 kDa)

Rapamycin
ATPCCI-779 competitive
RAD001 Inhibitors
AP23573

Figure 1 Structural domains of mTOR and molecular sites targeted by mTOR inhibitors.

its phosphotransferase activity. Intriguingly, both in vitro and in vivo studies

indicate that the FRB domain in mTORC2 is not accessible to rapamycins as
illustrated by the lack of suppression of phosphorylation of the mTORC2
substrate AKT. Rapamycins have single agent anti-tumor activity in various
tumor models, particularly those with a heightened PI3K/AKT/mTOR status or
deregulated angiogenesis signaling [6]. In some cell types, activation of mTORC1
leads to repression of PI3K/AKT signaling. This negative-feedback loop can be
inhibited by the binding of rapamycins to mTORC1 resulting in increased PI3KAKT activity, a phenomenon that may not be desirable for cancer therapy [3,6].

2.2 Inhibition of mTORC1 and mTORC2

In vitro anti-proliferative effects of the rapamycins are generally modest and
variable in cancer cells, in part due to their inaccessibility to mTORC2 and the
feedback-activation of PI3K/AKT signaling. In contrast, ATP-competitive
inhibitors of mTOR kinase targeting both mTORC1 and mTORC2 (Figure 1),
suppress mTOR signaling globally in cancer cells and in elements of the tumor
microenvironment, and minimize the feedback activation of PI3K signaling.
These properties of ATP-competitive inhibitors may provide new opportunities
for more robust anti-tumor efficacy in a broader range tumor types.

3. RAPAMYCIN ANALOGS IN THE CLINIC

The discovery of the immunosuppressive activity of rapamycin in the 1980s,
coupled with its unique mechanism of action, led to extensive structureactivity
relationship (SAR) investigations (reviewed in [10, 11]). Most of these early
investigations were done by semi-synthesis. Modifications of the 42-hydroxy
group gave rise to three new analogs currently in the clinic, temsirolimus (2, CCI779, Torisels), everolimus (3, RAD001), and deforolimus (4, AP23573, MK-8669)
(Figure 2).

3.1 Temsirolimus (CCI-779, Torisels)

Temsirolimus (2) is a soluble 42-[2,2-bis(hydroxymethyl)]-propionic ester
of rapamycin. The Food and Drug Administration (FDA) approved the use

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OR
X = Y = CH2; W = C=O

42
O

R=H
O

OH

Y
X

FKBP12

R=

R=

R=

OH

OH

N
O
W

HO
O

OH

9 R = H; X = S; Y = CH2; W = C=O
10 R = H; X = CH2; Y = S=O; W = CH2
mTOR FRB Domain

Figure 2 Rapamycin (1), temsirolimus (2), everolimus (3), and deforolimus (4). Precursor
directed biosynthesis derived analogs 9 and 10.

of temsirolimus for the treatment of advanced renal cell carcinoma (RCC) in

May 2007. In a phase III trial with 626 RCC patients, single-agent temsirolimus
was associated with a statistically significant improvement in overall survival
[12]. Phase II studies evaluating temsirolimus in a broad range of tumors have
also been reported. The most promising activity has been seen in mantle cell
lymphoma (MCL) [13] and endometrial carcinoma [14] with objective tumor
response rates of 30%40%. Moderate activity was reported for metastatic breast
cancer [15] and recurrent glioblastoma multiforme [16]. Minimal activity was
reported for metastatic melanoma [17]. In patients with advanced RCC,
temsirolimus response was associated with the phosphorylation of mTOR
pathway markers phospho-AKT and phospho-S6 [18]. In a breast carcinoma
study, the loss of PTEN and/or HER2 overexpression was also linked to
temsirolimus response [19]. However, while frequent loss of PTEN occurs in
melanoma and endometrial cancers, the lack of temsirolimus activity in
melanoma versus a strong response in endometrial cancer patients indicates
that molecular mechanisms other than PTEN status may determine the degree of
response.

3.2 Everolimus (RAD001)

Everolimus (3), 42-O-(2-hydroxyethyl)rapamycin, was developed to improve the
oral bioavailability of rapamycin [20]. Oral formulations of everolimus are being
evaluated in several late stage phase III trials in patients with pancreatic islet cell
tumors, and in phase II studies in patients with breast, lung, gastrointestinal, and
hematologic cancers [21]. In a phase II study of metastatic RCC, a partial response

mTOR Inhibitors in Oncology

193

rate of 33% was observed in the everolimus-treated patients [22]. Results of phase
I studies in hematologic, breast, nonsmall cell lung, and pediatric solid cancers
have been reported [2326]. In preclinical studies, everolimus demonstrated antitumor activity against MCL [27], pancreatic neuroendocrine tumors [28], and
ovarian tumors [29].

3.3 Deforolimus (AP23573, MK-8669)

Deforolimus (4), a dimethylphosphinate-modified rapamycin analog, is being
evaluated in a broad range of cancer trials, with promising results reported
for several tumor types. In a dose escalation phase I study, 22/29 patients
(76%) experienced stable disease or partial responses [30]. In a phase II study of
patients with advanced soft tissue or bone sarcomas, 54/193 (28%) achieved
a clinical benefit response (CBR) [31]. In two ongoing phase II studies in
patients with refractory hematologic malignancies, 41% and 55% had at least
stable disease [32,33]. In an ongoing phase II trial of advanced endometrial
cancer, 7 out of the first 19 patients (37%) achieved CBR [34].

4. PRE-CLINICAL RAPAMYCIN ANALOGS

Rapamycin analogs have been prepared primarily by semi-synthesis (reviewed
in [10,11]). Rapamycin has also been prepared by long and complex total
synthesis (e.g. [35]). Modifications of rapamycin by enzymatic methods, by
exploitation of the biosynthetic pathway, and by genetic manipulation have also
been utilized ([36] and references therein).
Recently, precursor directed biosynthesis has been applied to the generation of new rapamycin analogs [37]. This approach, also known as
mutasynthesis, couples chemical synthesis with molecular biology and is
especially useful for modification of complex natural products, such as
rapamycin, whose lengthy and complex total synthesis precludes ready lead
optimization. A mutant strain of Streptomyces hygroscopicus (MG2-10) that does
not generate 4,5-dihydroxycyclohex-1-ene carboxylic acid (DHCHC), the source
of the dihydroxycyclohexane moiety of rapamycin, allowed for the incorporation
of novel starter units in the biosynthesis of pre-rapamycin (5) and pre-rapamycin
analogs 68 (Figure 3) [3739]. Another approach to precursor-directed
biosynthesis utilized the observation that nipecotic acid inhibits the biosynthesis
of rapamycin, while concurrent feeding with l-pipecolate restores production.
Thus, feeding of sulfur-containing pipecolate analogs to cultures of
S. hygroscopicus along with nipecotic acid led to production of two new
sulfur-containing pipecolate analogs (9, 10) (Figure 2) of rapamycin [36]. Both
analogs were found to bind several orders of magnitude less tightly to FKBP12
than did rapamycin.

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Starter Unit

HO2C

R = R = OH

R = R = OH

R = R = H

R = OH; R = H

OH

N
O

O
HO
HO2C

OH

HO

OH
HO2C

Figure 3 Precursor directed biosynthesis of rapamycin analogs.

5. ATP COMPETITIVE mTOR INHIBITORS

5.1 Mixed mTOR/PI3K inhibitors
As described in the preceding section, the majority of reports on mTOR
inhibitors have dealt with rapamycin and its analogs. Small molecules that
interact with the ATP-binding site of mTOR have also recently been described.
As outlined in the introduction, these types of molecules would be expected to
inhibit both mTORC1 and mTORC2 complexes, whereas rapamycins inhibit
predominantly mTORC1. Unlike rapamycin, which due to its unique ternary
complex formation is a very selective inhibitor of mTORC1, most mTOR active
site inhibitors reported to date also inhibit one or more related kinases.
For example, SF1126 (11, Figure 4) is a vascular-targeted conjugate of the wellcharacterized PI3K/mTOR/DNA-PK inhibitor LY294002 [40]. The structure
of SF1126 shown in Figure 4 is based on an X-ray crystal structure [41].
The previously published structure of SF1126 showed the tripeptide linked
to LY294002 through the morpholine nitrogen [40]. In 2007, Phase I clinical trials
studying SF1126 in patients with solid tumors and multiple myeloma were
initiated [41].
LY303511 (12, Figure 4), historically considered an inactive analog of
LY294002 due to its lack of PI3K inhibition, displayed a biomarker profile in
A549 cells suggestive of mTOR inhibition without PI3K inhibition [42].
In addition to mTOR, 12 inhibited casein kinase 2. Despite its relatively low
potency (micromolar concentrations were required for inhibition of mTOR
biomarkers in tumor cells), LY303511 inhibited tumor growth in a xenograft
model of human adenocarcinoma (PC-3) following i.p. administration at
10 mg/kg, q.d.

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O
Arg-Gly-Asp-Ser
O

O
N
O

N
Cl

N
O

13

11
12 X = NH
LY-294002 X = O

Figure 4 mTOR inhibitors derived from the prototypical pan-PI3K/mTOR inhibitor LY294002.

OH
AcO
MeO

O
H
O

O
OH
14

Figure 5

mTOR inhibitor derived from the pan-PI3K/mTOR inhibitor wortmannin.

Another analog of LY294002, 13 (Figure 4), inhibited DNA-PK and mTOR,

without inhibiting PI3K [43]. In Rat-1 fibroblasts, 13 inhibited the activity of both
mTORC1 and mTORC2 as demonstrated by inhibition of the phosphorylation
of S6K1 Thr-389 and AKT Ser-473.
Analogs of another well-known pan-PI3K/mTOR inhibitor, wortmannin,
were recently reported [44]. Ring-opening of the furan ring of 17-hydroxywortmannin with secondary amines led to analogs with improved stability, toxicity,
and aqueous solubility versus wortmannin. As with wortmannin, these analogs
(e.g. 14) (Figure 5) inhibited mTOR, albeit several orders of magnitude less
potently than PI3K-alpha.
Mixed inhibitors of mTOR and PI3K have also been developed from new
scaffolds. For example, it was recently shown that the PI3K inhibitor PI-103
(15, Figure 6) inhibits both mTORC1 and mTORC2 at low nanomolar
concentrations (IC50 values of 2080 nM) [45,46]. PI-103 was more effective
in vivo in glioma xenograft models as compared to selective PI3K-alpha
inhibitors, which was ascribed to its additional effects on mTOR [46].
NVP-BEZ-235 (16, Figure 6), a potent mixed inhibitor of PI3K and mTOR with
low nanomolar IC50 values against both enzymes [47,48] was active in A549
(lung) and BT474 (breast) xenograft models following oral dosing. Compound 16
is reportedly in phase I clinical trials.

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O
R

NC
N
O

NH
O

OH
N

15

16

S
N
H O

17
N

Figure 6 Mixed PI3K and mTOR inhibitors in advanced stages of development.

O
N

O
H
N

HN
S

O
S

19

18
N

H
N

HN

Cl

O
Cl

NH
H
N

O
H
N

N
N

H
N

S
N

O
N

20

N
Cl

21

O
Cl

Figure 7 3-Aryl-5-sulfonamidopyridine mixed mTOR/PI3K inhibitors.

XL-765 (structure undisclosed) is also a mixed mTOR/PI3K inhibitor reported

to be in clinical development. XL-765 inhibits the various isoforms of PI3K with
IC50 values of 9113 nM and inhibits mTOR with an IC50 of 157 nM [49]. Exelixis
has recently filed a patent application on substituted N-[3-aryl-quinoxalin-2-yl]benzenesulfonamides (cf. 17, Figure 6) as PI3K-alpha inhibitors [50].
The recent patent literature contains several reports on 3-aryl-5-sulfonamidopyridines as mixed PI3K/mTOR inhibitors (Figure 7). Both the methanesulfonyl derivative 18 and the benzenesulfonyl analog 19 inhibited PI3K-alpha and
mTOR with IC50 values of 10 nM [51,52]. The orientation of the sulfonamide bond
was important for mTOR inhibitory activity as reversal of the sulfonamide
bond significantly decreased the mTOR potency. Compound 19 gave 20% tumor
regression following 0.5 mg/kg p.o. dosing in nude mice in a PC3 tumor
xenograft model [53].
Two additional patent applications disclosed 3-aryl-5-sulfonamidopyridines
as well, although very limited biological data were presented. Thus, compound

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N
N

N
H

HO

22

N
23

N
R

Figure 8 Substituted pyrimidine mixed PI3K/mTOR inhibitors.

20 had IC50 values against PI3K-alpha and mTOR of 0.51 mM [54]. Compound 21
inhibited mTOR with an IC50 of 2 mM and was slightly more potent against PI3Kalpha (IC50 0.5 mM) [55].
Patent applications disclosing substituted pyrimidines have appeared.
Although no specific inhibitory activities are provided, compounds such as 22
(Figure 8) are claimed to inhibit PI3K and/or mTOR with IC50 values between
1 and 500 nM [56]. Similarly, compounds such as 23 possess potent inhibitory
activity against mTOR and PI3K-alpha [57].

5.2 Selective mTOR inhibitors

Recently, several patent applications claimed mTOR inhibitors without claims
of PI3K activity. 4-Morpholin-4-yl-pyrido[2,3-d]pyrimidines inhibited mTOR at
nanomolar concentrations [58,59]. For example, compound 24 (Figure 9) had an
mTOR IC50 of 43 nM. Substituted morpholino-triazines, such as 25, with IC50
values against mTOR below 1.5 mM, have also been reported [60]. KU-0063794
(structure undisclosed) was reported to be a highly potent inhibitor of mTOR
(IC50 16 nM) with W100-fold selectivity versus other PIKK members
(e.g. PI3Kalpha, DNA-PK, ATM, ATR) [61].
3-Alkyl-1-alkynyl-imidazo[1,5-a]pyrazin-8-ylamines, such as compound 26,
have been disclosed as mTOR inhibitors with IC50 values below 10 mM [62].
Several 3-alkyl-1-aryl-imidazo[1,5-a]pyrazin-8-ylamines, such as 27, possessed
IC50 values below 10 nM [63]. The effect on related kinases was not reported in
these patent applications. Replacement of the imidazopyrazine core of the above
compounds with a 1H-pyrazolo[3,4-d]pyrimidine group led to analogs (e.g. 28 in
Figure 9) with mTOR IC50 values below 1 mM that also inhibited several other
kinases (cKIT, Tie2, FLT3, PDGFR, RET, and IR) with nanomolar IC50 values [64].
OXA-01, an imidazopyrazine (structure undisclosed), inhibited mTORC1 and
mTORC2 with IC50 values of 29 and 7 nM, respectively [65]. In an MDA-MB-231
xenograft model, 100% tumor growth inhibition was seen with 75 mg/kg p.o. bid
dosing of OXA-01 for 14 days.

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OH
OH

MeO

N
N

N
O

24

HO

N
H

OH

25

OMe

HN
N
NH

NH2

NH2

NH2
N

26

27

28

Figure 9 mTOR inhibitors from recent patent literature.

O
H
N

H
N

HO
O

O
29

Figure 10 HTS-1, a non-rapamycin derived FRB domain binder.

6. OTHER mTOR INHIBITORS

Compound HTS-1 (29) (Figure 10) was obtained from a high-throughput screen
for binders to the FRB domain [66]. NMR solution structural studies revealed
that the sites on the mTOR FRB domain that interact with HTS-1 closely match
those that are responsible for rapamycin binding. The dissociation constant for
compounds of this type is in the low micromolar range [66].
Other publications claim inhibition of mTOR signaling pathways, but
do not show evidence of direct inhibition of mTOR. Hence, inhibition of
upstream effectors, rather than mTOR itself, cannot be excluded. For example,

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HO
N

OH

O
R
N
H

N
H

30

O
Cl

N
H

HN

32

NH

31

Figure 11 mTOR signaling pathway inhibitors.

pyrido[2,3-b]pyrazin-6-yl-ureas (cf. 30, Figure 11) that inhibit signaling

pathways and enzymes, including mTOR, were disclosed [67,68]. 3,3-Diaryl1,3-dihydro-indol-2-one inhibitors of mTOR pathway activation (e.g. 31) showed
efficacy in xenograft models of human tumors [69]. Beta-elemene derivatives
such as 32 were reported to have an anti-proliferative effect on tumor cells at low
micromolar concentrations, due to their inhibition of mTOR activity [70].

7. CONCLUSION
Through the success of rapamycin analogs (i.e. 2, 3, 4) in the clinic, mTOR has
been firmly established as a therapeutic target for the treatment of cancer. The
unique mechanism of mTOR inhibition by rapamycin and its analogs through
binding to the FRB domain and formation of a ternary complex with FKBP12
make these compounds extremely selective for the complex mTORC1 with
relatively little inhibition of mTORC2. Recently, ATP competitive inhibitors
of mTOR have been shown to inhibit both complexes of mTOR and may offer
clinical advantages in treating tumors that are not sensitive to rapamycin analogs.

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