Non-substrate based, small molecule inhibitors of the human isoprenylcysteine carboxyl methyltransferase

Article abstract of DOI:10.1039/c6md00130k

Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The human isoprenylcysteine carboxyl methyltransferase (hIcmt) enzyme catalyzes the final α-carboxyl methylesterification of the C-terminal farnesyl cysteine of K-Ras, which is necessary for its proper localization. Thus, hIcmt inhibition is a regarded as a promising cancer therapy. A high quality inhibitor of hIcmt with in vivo activity would advance hIcmt research and drug development. Herein, Wwe report the results of a screen for small molecule hIcmt inhibitors in a library of molecules that were not hIcmt substrate analogs. The lead compound identified by this screen (1) was modified to remove chemical liabilities and to increase potency. The most potent resulting compound (5) inhibited hIcmt in vitro with low micromolar potency (IC₅₀ = 1.5 ± 0.2 μM) and was kinetically characterized as a competitive inhibitor for prenylated substrates and a non-competitive inhibitor for the cofactor and methyl donor S-adenosylmethionine (SAM). These inhibitors offer important structure activity relationships for the future development of hIcmt inhibitors with in vivo activity.

Full text of DOI:10.1039/c6md00130k

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RESEARCH ARTICLE
Non-substrate based, small molecule inhibitors of
the human isoprenylcysteine carboxyl
methyltransferase†‡
Cite this: DOI: 10.1039/c6md00130k
a
b
b
a
Kyle V. Butler,§ Kelsey Bohn,§ Christine A. Hrycyna* and Jian Jin*
Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present
in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma
membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The human iso-
prenylcysteine carboxyl methyltransferase (hIcmt) enzyme catalyzes the final α-carboxyl methyl-
esterification of the C-terminal farnesyl cysteine of K-Ras, which is necessary for its proper localization.
Thus, hIcmt inhibition is a regarded as a promising cancer therapy. A high quality inhibitor of hIcmt with
in vivo activity would advance hIcmt research and drug development. Herein, Wwe report the results of a
screen for small molecule hIcmt inhibitors in a library of molecules that were not hIcmt substrate analogs.
The lead compound identified by this screen (1) was modified to remove chemical liabilities and to increase
potency. The most potent resulting compound (5) inhibited hIcmt in vitro with low micromolar potency
Received 2nd March 2016,
Accepted 5th April 2016
(
IC50 = 1.5 ± 0.2 μM) and was kinetically characterized as a competitive inhibitor for prenylated substrates
and a non-competitive inhibitor for the cofactor and methyl donor S-adenosylmethionine (SAM). These in-
hibitors offer important structure activity relationships for the future development of hIcmt inhibitors with
in vivo activity.
DOI: 10.1039/c6md00130k
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amino acids, usually Ser, Met, Ala, Gln, or Leu) by
farnesyltransferase (FTase I); the three C-terminal residues are
Introduction
Small molecule inhibitors of K-Ras oncoproteins are perhaps
the most sought after compounds in oncology drug discovery,
as these proteins carry activating mutations in about 30% of
human cancers. Possibly due to the high affinity of K-Ras for
GTP and the high concentrations of GTP in cells, direct inhibi-
proteolyzed by Ras-converting enzyme 1 (Rce1); finally, iso-
prenylcysteine carboxyl methyltransferase (Icmt) catalyzes trans-
fer of a methyl group from S-adenosylmethionine (SAM) to the
terminal cysteine carboxy terminus, resulting in formation of a
1
,2
6–10
methyl ester.
Inhibiting any of these processing events dis-
11
tion of K-Ras has been difficult to achieve, although novel in-
rupts Ras localization and its ability to stimulate cell growth.
G12C
hibitors of K-Ras
have been described recently that target a
Inhibitors of FTase have potent anticancer properties in vitro,
3
separate binding pocket on the enzyme. K-Ras must be local-
ized to the plasma membrane to properly function. Therefore,
molecules that interfere with its localization could be effective
inhibitors. In order to be localized to the plasma membrane,
newly synthesized K-Ras is modified posttranslationally by se-
quential prenylation, proteolytic and methylation reactions.
K-Ras is first isoprenylated on the C residue of its CaaX motif
but have failed in clinical trials due to alternative prenylation
1
of Ras by geranylgeranyltransferases. Effective inhibitors of
hIcmt would be desirable therapeutics. Genetic ablation of Icmt
in mice causes mislocalization of Ras and inhibits the cell pro-
liferation and transformation caused by activating Ras muta-
4,5
12,13
tions.
hIcmt inhibitors may also be useful as treatments for
Hutchinson-Gilford progeria syndrome (HGPS). HGPS results
from accumulation of the CaaX-containing protein prelamin A
at the nuclear envelope. A hypomorphic hIcmt allele prevented
appearance of the HGPS phenotype in mice carrying the
(where C = cysteine, a = aliphatic residue, X = one of several
a
Departments of Structural and Chemical Biology, Oncological Sciences, and
14
progeria-causing ZMPSTE24 deficiency.
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount
Sinai, New York, New York 10029, USA. E-mail: jian.jin@mssm.edu
Multiple hIcmt inhibitor chemotypes have been reported,
b
15–20
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette,
most of which are either substrates or substrate analogs.
Indiana 47907, USA. E-mail: hrycyna@purdue.edu
There are few reports of hIcmt inhibitors that are not based
on farnesylated substrates, including members of the tetra-
†
‡
The authors declare no competing interests.
Electronic supplementary information (ESI) available. See DOI: 10.1039/
2
1–26
hydropyranyl series and cysmethynil and its analogs.
The
c6md00130k
These authors contributed equally to this work.
§
tetrahydropyranyl compounds were shown to have low
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nanomolar potency in vitro, but lacked robust antiproliferative
activity. Cysmethynil, which is the most well-characterized
IC50 of 7.7 μM. Replacing the hydroxynaphthalene with naph-
thalene resulted in a further gain in potency. The tertiary alco-
hol compound 4 has an IC50 of 2.2 μM and the alkene 5
(Fig. 2) has an IC50 of 1.5 μM. Thus, the problematic lead com-
pound, 1, was transformed into a compound lacking the origi-
nal liabilities, with a ∼9-fold increase in potency.
2
1
hIcmt inhibitor, has an in vitro IC50 of 1.5 μM and causes Ras
2
2,23
mislocalization in cells at micromolar concentrations.
These molecules are currently being used successfully as tools
to interrogate pathways and the cellular role of iso-
2
7
prenylcysteine methylation but not as therapeutics. Unfortu-
nately, thus far, inhibitors of hIcmt with both high potency
and robust cellular activity have not been identified. Thus,
there is an urgent need for hIcmt inhibitors with potent
in vivo activities for cancer and progeroid disorder drug discov-
ery. To meet this need, we developed a series of non-substrate
hIcmt inhibitors featuring a novel chemotype. The most potent
compound in this series has an in vitro IC50 value of 1.5 ± 0.2
μM, shows competitive inhibitory kinetics for a farnesylated
substrate and non-competitive kinetics for the cofactor SAM.
We next attempted to modify the thiophene portion of the
molecule. Replacement of thiophene with phenyl gave the in-
active compound, 6. Removal of the thiophene, as in com-
pounds 7 and 8, also abolished activity. We also attempted to
further minimize the lead by replacing naphthalene with a
phenyl group, giving compounds 9 and 10. However, both
were inactive. The most potent compound, 5, has a clog P
value of 4.9 and is very planar. Both of these factors will de-
crease compound solubility, and consequently, may compro-
mise in vivo potency. We sought to improve solubility by re-
placing the ether oxygen with a protonatable nitrogen and by
saturating the alkene. The resulting compounds, 11 and 12,
however, were not active. The non-substrate analog inhibitors
were not as potent as some previously reported substrate ana-
Results
Screening
To identify novel hIcmt inhibitors, we screened a library of 700
compounds in an in vitro vapor diffusion assay developed for
hIcmt activity. Crude membrane extracts expressing human
15
logs like FTPA Triazole 10n.
In order to determine the mode of inhibition by 5, our most
potent compound, detailed kinetic assays were performed
using crude yeast membrane preparations expressing hIcmt.
Lineweaver–Burk analyses demonstrated that 5 is a competitive
inhibitor with the hIcmt minimal substrate, N-acetyl-S-farnesyl
15
Icmt (hIcmt) were prepared as described. The library was com-
posed of commercially available compounds and also com-
pounds synthesized as part of ongoing methyltransferase inhib-
itor drug discovery projects, including the soluble histone
I
cysteine (AFC) (K = 1.1 ± 0.2 μM) and a non-competitive inhibi-
2
8–34
methyltransferases G9a and SETD8.
fusion assay for hIcmt activity for both the primary screen of
We used the vapor dif-
tor with SAM (K = 2.9 ± 0.2 μM) (Fig. 3).
I
Cell killing assays were conducted to assess the ability of 5
to inhibit the growth of MIA-PaCa2, a pancreatic cancer cell
line expressing a G12C K-Ras mutation. Compound 5 MIAPaCa
cells with an IC50 of 31.9 ± 2.3 μM. Compound 5 killed Panc-1
cells (G12D mutant K-Ras) with an IC50 of 78 μM.
7,15
the inhibitors and for subsequent IC50 determination.
For
the screen, compounds were assayed at a single concentration
of 10 μM. Any compound that reduced activity to less than 15%
of the wild-type control was considered for further screening.
Confirmed hits were subjected to an IC50 determination assay.
The most potent of this group was compound 1, which demon-
strated an IC50 value of 14 μM (Fig. 1). Compound 1 was synthe-
sized by the Petasis multicomponent reaction, and compounds
of this type are frequently found in commercially available HTS
collections. We had several initial concerns with 1 as a lead
compound. Phenolic Mannich-bases like 1 are known to be
pan-assay interference compounds and are sometimes false
Discussion
Screening of a library of 700 unique compounds identified
the lead, 1, as an inhibitor of hIcmt with an IC50 of 14 μM in
an in vitro methyltransferase assay. The structure of 1 was
modified to replace the labile C–N bond and to replace the
phenolic Mannich base functional group associated with as-
say interference. This process led to the most potent com-
pound in this series, 5, with an IC50 value of 1.5 μM (Fig. 1
and 2). The in vitro IC50 value of 5 is similar to the reported
35
leads for drug discovery. Also, the compound can readily de-
compose in acidic solution through the retro-Mannich pathway.
We modified the structure in order to nullify these liabilities as
described below (Fig. 1).
23
for the well-characterized hIcmt inhibitor, cysmethynil. All
but two of the hydrogen-bond forming atoms were removed
in the transformation of the original lead to 5, leaving a pla-
nar, hydrophobic compound. Efforts to decrease the clog P of
5 or to add solubility-enhancing groups were unsuccessful.
Compound 5 is much more simple than the parent 1, and
has only two hydrogen bond acceptors. The high ratio of C/H
atoms relative to heteroatoms in 5 suggests that its affinity
for hIcmt is largely entropy-driven. It is likely that functional
groups could be added to 5 that would form hydrogen bonds
with hIcmt, improving the enthalpy component of the bind-
ing affinity, but in the absence of a co-crystal structure,
Medicinal chemistry
The C–N bond of 1 is labile, and we removed this liability by
removing the nitrogen. Additionally, we replaced the problem-
atic hydroxyquinoline chemophore with hydroxynaphthalene.
Synthesis was accomplished by sequential nucleophilic attack
on a Weinreb amide, followed by dehydroxylation of the
resulting tertiary alcohol. The resulting compound, 2, had an
in vitro IC50 of 18 μM, similar to the lead. Saturation of the
C–C bond linking the two arenes and the tetrahydropyran, as
in the alkene-containing analog, 3, increased the potency to an
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Fig. 1 Structures and IC50 values of compounds. Compounds containing a stereocenter were prepared as the racemate. Assays were conducted
three separate times in duplicate. a.) The FTPA triazole is shown for comparison.
rationally introducing such groups would be difficult. The
crystal structure of an hIcmt ortholog has been solved, how-
ever homology only exists to the C-terminal half of the en-
zyme and does not include the prenylated substrate binding
a structurally similar but more potent inhibitor. This result
demonstrates that PAINS structures can serve as viable leads for
drug discovery, as has been noted by Baell et al.
A Lineweaver–Burk plot revealed 5 to be competitive with
the prenylated peptide substrate, AFC and non-competitive
with SAM. The substrate-competitive enzyme inhibition of
Icmt is inherently druggable, as the enzyme must present a
large nonpolar surface to bind the farnesyl group, concomi-
37
3
6
site.
The lead compound 1, contains a known pan-assay inter-
ference (PAINS) functional group. PAINS interfere nonspecifically
in multiple, unrelated biochemical assays. Optimization of these
compounds by medicinal chemistry frequently wastes resources.
However, the PAINS functional group of 1 was removed, yielding
tantly presenting
molecules.
a
binding site for lipophilic small
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Fig. 2 Synthesis of 5.
Fig. 3 Compound 5 is competitive with AFC and non-competitive with SAM. (A) Specific activity of ICMT was determined with increasing concen-
trations of AFC for varying concentrations of 5 while keeping SAM concentration constant at 5 μM. (B) Specific activity of hIcmt was determined
14
with increasing concentrations of [ C]-SAM for varying concentrations of 5 while keeping AFC concentration constant at 25 μM.
Conclusions
are urgently needed. The inhibitors described in this work
could serve as useful leads for drug development towards
the discovery of highly effective hIcmt inhibitors. We have
significantly advanced the potency of this series of com-
pounds with a few functional group substitutions. We
Potent and effective inhibitors of hIcmt could be useful
treatments for K-Ras-driven malignancies. No clinically effec-
tive inhibitors of K-Ras function exist, so these treatments
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in high potency inhibitors.
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