Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Article abstract of DOI:10.1002/cmdc.201800271

The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure–activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure–degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

Full text of DOI:10.1002/cmdc.201800271

Accepted Article
Title: Efficient Synthesis of Immunomodulatory Drug Analogues
Enables Exploration of Structure Degradation Relationships
Authors: George M Burslem, Philipp Ottis, Saul Jaime-Figueroa, Alicia
Morgan, Philipp Cromm, Momar Toure, and Craig Crews
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201800271
Link to VoR: http://dx.doi.org/10.1002/cmdc.201800271
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10.1002/cmdc.201800271
ChemMedChem
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Efficient Synthesis of Immunomodulatory Drug Analogues
Enables Exploration of Structure Degradation Relationships
G.M. Burslem,*[a] P. Ottis,[a] S. Jaime-Figueroa,[a] A. Morgan,[b] P.M. Cromm,[a] M. Toure,[a] and C.M.
Crews*[a,c]
Abstract: The Immunomodulatory Drugs (IMiDs) Thalidomide,
Pomalidomide and Lenalidomide have been approved for the
treatment of multiple myeloma for many years. Recently, their usage
as E3 ligase recruiting elements for small molecule induced protein
degradation has led to a resurgence in interest in ImiD synthesis and
functionalization. Traditional ImiD synthesis follows a step-wise route
employing multiple purification steps. Herein, we describe a novel
one-pot synthesis without purification giving rapid access to a
multitude of IMiD analogues. Binding studies with the IMiD target
protein Cereblon (CRBN) reveals a narrow SAR with only a few
compounds showing sub-micromolar binding affinity in the range of
Pomalidomide and Lenalidomide. However, anti-proliferative activity
as well as Aiolos degradation could be identified for two ImiD
analogues. This study provides useful insight into the structure
degradation relationships for molecules of this type as well as a rapid
and robust method for IMiD synthesis.
for proteolysis targeting chimera (PROTACs).16, 17 Indeed ImiD
drugs have been widely employed as E3 recruiting elements to
enable the degradation of a wide variety of targets.18-25
Intrigued by the “molecular glue” mechanism of these compounds
we sought to explore the structure degradation relationships of
ImiD analogues with an aim to elucidate the requirements for neo-
substrate recruitment and the development of high affinity
recruiting elements for use in PROTACs. Previous SAR studies
have proven challenging due to both time-consuming synthesis
and insufficient knowledge surrounding the mechanism of action
prior to 2014.
Thalidomide, Pomalidomide and Lenalidomide, collectively
known as Immunomodulatory Drugs (IMiDs), have been
employed to treat multiple myeloma for many years.1-4 For the
majority of this time, the molecular mechanism of action was
unknown rendering attempts to explore the structure activity
relationships challenging.5, 6 In recent years, the elucidation of the
unique mechanism of action of these compounds has caused a
resurgence of interest in IMiDs.7-11 These compounds function by
inducing ectopic protein-protein interactions between Cereblon, a
substrate recognition component of the CRL4 E3 ligase complex,
and un-natural substrates (Ikaros, Aiolos and CK1α)9-11, resulting
in ubiquitination and subsequent degradation of the neo-substrate
(See Figure 1). The fundamental understanding of the
mechanism has enabled the discovery of analogues which induce
Figure 1 – Crystal structure of the complex between CRBN (blue) and CK1α
(green) with Lenalidomide mediating the interface (PDB ID: 5FQD) and the
structures of the ImiDs.
degradation of additional proteins, namely the translation
13
termination factor GSPT1.12,
Recently, a family of aryl
Confronted by the challenge of developing a rapid and robust
synthesis of IMiD analogues we surveyed the literature. The
majority of routes employ the cyclisation of glutamine and
condensation with an anhydride to yield the desired scaffold.
Preparation of Boc-2-aminoglutarimide can be achieved by the
treatment of N-α-(tert-butoxycarbonyl)-L-glutamine (Boc-Gln) with
sulfonamide molecules which function via a distinct but similar
mechanism have also been reported.14, 15 Molecules which bind
to an E3 ubiquitin ligase are also of great interest to the field of
targeted protein degradation, particularly as recruiting elements
1,1-Carbonyldiimidazole
(CDI)
and
catalytic
4-
[a]
Dr. G.M. Burslem, Dr. P. Ottis, Dr. S. Jaime-Figueroa, Dr. P.M.
Cromm, Dr. M. Toure and Prof. Dr. C.M. Crews
Department of Molecular, Cellular and Developmental Biology
Yale University
219 Prospect Street, New Haven, CT, USA
E-mail: George.Burslem@Yale.edu
Craig.Crews@Yale.edu
Dr. A. Morgan
Arvinas LLC
5 Science Park, New Haven, CT, USA
Prof. Dr. C.M. Crews
(Dimethylamino)pyridine (DMAP) in THF at reflux temperature as
previously reported.†26 Previous routes have employed step-wise
deprotection and condensation reactions to yield the desired
scaffold in moderate yields following purification.26, 27 Alternatively,
the condensation reaction can be performed before cyclisation of
the glutarimide.28, 29
[b]
[c]
Departments of Chemistry and Pharmacology,
Yale University, New Haven, CT, USA
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cmdc.201800271
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Entry
Solvent
Trifluoroethanol
Ethanol
Temperature / °C
Isolated Yield
91%(a)
1
2
3
150
150
150
24%(a)
10% TFA in Ethanol
Complex
Mixture(a)
4
5
6
Trifluoroethanol
Trifluoroethanol
Trifluoroethanol
Reflux
150
No Reaction(b)
72%(c)
150
62%(a)(d)
[a] heated under microwave conditions [b] heated in an oil bath [c] heated
in an oil bath at 150° in a seal tube [d] phthalic acid used in place of
phthalic anhydride
Scheme 1 – Synthesis of Thalidomide and screening of reaction conditions.
To expedite the process, we sought to combine a thermal BOC
deprotection with the condensation step. Since 2,2,2-
trifluoroethanol (TFE) can afford t-butoxycarbamate (BOC)
deprotection at high temperature, we attempted the one pot
procedure shown in Scheme 1, entry 1.30 Gratifyingly, the reaction
proceeded to completion under these conditions and, upon
cooling to room temperature, the product precipitated to provide
analytically pure compound in high yield. Exploring the role of the
reagent/solvent in this reaction exemplifies the advantage of
employing TFE as a solvent in this reaction. Switching to ethanol
results in a significantly reduced yield as the deprotection step is
considerably less efficient in the less acidic solvent. Notably
addition of trifluoroacetic acid results in a complex mixture of
unidentified products. Heating of the reaction to reflux in TFE for
2 hours results in no deprotection of the BOC group and hence
no subsequent condensation. Submersion of the reaction vessel
in an oil bath at 150 °C for 2 hours rather than microwave
irradiation results in a slightly reduced yield which can likely be
attributed to less efficient heating. Interestingly, the use of phthalic
acid in place of the anhydride is tolerated due to in-situ formation
of the anhydride. ‡
Figure 2 – Structures of compounds prepared in this study with corresponding
reaction yields. [a] Prepared by hydrogenation of compound 16.
Having explored conditions for the synthesis of Thalidomide, we
employed these optimized conditions to prepare a library of
analogues in a rapid and chromatography-free manner (see
Figure 2) from commercially available anhydrides. These
conditions proved to be relatively general and tolerate a variety of
functional groups. Hetero-aromatic anhydrides were well
tolerated as were substitutions in both the 3- and 4- positions.
Bicyclic and fused ring systems as well as various degrees of
saturation are also tolerated. Notably, we were able to prepare
Pomalidomide (compound 13) in one step from commercially
available starting materials in an 80% yield with no purification
step required. To the best of our knowledge, this is the first
synthesis of Pomalidomide avoiding the use of nitro-group
reduction as the aniline is tolerated under these conditions.
Furthermore, this approach can also be employed to prepare
SEM protected 21 or N-methylated 22 analogues.
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10.1002/cmdc.201800271
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of the neo-substrates Aiolos and CK1α.31 To this end MM-1S cells
were treated with 10 μM of each compound for 24 hours before
immunoblotting for the target proteins. Pomalidomide,
Lenalidomide and Thalidomide were included as positive controls
while DMSO served as a negative control.
Table 1. Binding constants for compounds to CRBN measured by surface
plasmon resonance and their ability to induce degradation of neo-substrates
Aiolos and CK1α at 10 µM.
Degradation
Compound
CRBN Kd / nM[a]
445 ± 19
264 ± 18
>11000
N.B.
Aiolos
CK1α
Lenalidomide
+
+
-
+
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Pomalidomide
1
2
-
3
N.D.
-
4
N.D.
-
5
N.D.
-
6
1450 ± 49
1400 ± 375
55 ± 18
N.B.
-
7
-
8
-
9
-
10
11
12
13
14
15
16
17
18
19
20
N.D.
-
221 ± 52
111 ± 6
271 ± 110
N.D.
-
-
+
-
N.D.
-
>11000
558 ± 51
2100 ± 400
325 ± 24
549 ± 66
-
Figure 3 - Cellular evaluation of selected compounds. A – Normalized Aiolos
levels in MM1S cells after 24 hours treatment with the indicated dose as
assessed by Western Blotting and normalized to Tubulin. The dashed line
represents non-linear regression for the calculation of DC50. B – Inhibition of cell
proliferation of selected compounds after 72 hours as measured by MTS assay.
+
-
+
-
Compounds 17 and 19 which were capable of inducing
degradation of Aiolos at 10 µM were further evaluated in dose-
response experiments via immunoblotting. Quantification of the
bands and normalization to tubulin loading controls allows the
calculation of DC50 values (the concentration at which half
maximal degradation is observed) and DMax (the maximal
degradation achieved) (Fig 3A). Replacement of the aniline
moiety in Pomalidomide (DC50 – 8.7 nM, Dmax > 95%) results in a
loss of activity in the case of the methyl derivative compound 19
(DC50 – 120 nM, Dmax - 85%) and a more pronounced loss of
activity in the fluoride compound 17 (DC50 – 1400 nM, Dmax - 83% ).
Compounds 17 and 19, which displayed interesting degradation
characteristics, were progressed to cell proliferation assays in
MM1S cells and compared to Lenalidomide and Pomalidomide
(Fig. 3B). Both the new compounds were able to inhibit cell
proliferation at similar doses to their corresponding DC50 values
(Compound 19 IC50 – 128 nM, Compound 17 IC50 – 3568 nM).
This small analogue library reveals the exquisite requirements of
compounds which induce interactions between CRBN and the
neo-substrates, Aiolos and CK1α. Small substituents are
tolerated at the 4 position with the curious exception of a hydroxy
group (Compound 14). The surprisingly lack of activity with
Compound 14 could conceivably be due to perturbation of a local
N.B – no binding observed, N.D. – Not determined due to
reference cell binding
[a] – Average of at least 2 experiments. Errors represent the
standard error of the mean.
Having unprecedented access to novel analogues of ImiDs we
sought to explore the structure-activity relationships with respect
to CRBN binding and the degradation of Aiolos (IKZF3) and CK1α.
To assess binding of ImiD analogues to CRBN directly, we
employed an SPR assay with His-tagged CRBN immobilized.
Dose-response curves were measured for each analogue and Kd
values calculated. The results are summarized in Table 1. This
direct binding analysis revealed that many of the newly
synthesized ImiDs retain the ability to bind CRBN, indeed several
of them (Compounds 8 and 12) have a higher affinity than the
FDA approved compounds employed as positive controls. For
example, the 1,8-Naphthalic anhydride derived compound 12
shows a higher affinity for CRBN presumably due to increased
hydrophobic interactions with the protein surface. Molecular
modelling revealed that compound 12 is able to adopt the same
binding conformation as pomalidomide (see S.I.)
In addition to measuring the binding to CRBN, we sought to
explore the ability of these new analogues to induce degradation
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10.1002/cmdc.201800271
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COMMUNICATION
hydrogen bonding network. Substitution elsewhere on the
aromatic ring or deviation from an isoindoline core perturbs
recruitment of the known neo-substrates. Perhaps unsurprisingly
given the mechanism of action, affinity for CRBN appears not to
be the sole determinant for neo-substrate degradation, as some
molecules binds to CRBN with an increased affinity yet fail to
induce degradation. Indeed, even amongst the compounds which
do induce degradation, CRBN affinity appears not to be predictive
of cellular activity – Compound 17 binds with roughly 2-fold less
affinity than Pomalidomide and Compound 19 however both
Compounds 17 and 19 have greatly reduced effect on protein
degradation and proliferation when compared to Pomalidomide.
More important are structural changes which, even when subtle,
can completely abrogate the degradation of the neo-substrate.
This is most likely due to perturbation of the required protein-
protein interaction as even subtle changes, such as fluorination in
the 5 position (Compound 8), drastically effecting hydrophobicity
of the combined protein/ligand surface (see S.I.) and presumably
therefore prevent trimer formation. A similar change in surface
characteristics may also be responsible for the reduced activity of
compound 17 compared to thalidomide, although to a lesser
extent since the 4 position is less buried at the interface. These
subtle differences highlight the inherent difficulty in designing
molecular glues.
In summary, we report a rapid, chromatography free synthesis of
2 FDA approved drugs as well as more than 20 additional
analogues, along with the structure degradation relationships
(SDR) for these new compounds which highlight the inherent
challenge in developing molecules which function via this
mechanism. We identified two previously uncharacterized
thalidomide analogues with anti-proliferative activity in a cellular
multiple myeloma model. Furthermore, we have identified several
compounds with improved pharmacological properties and/or
increased CRBN binding affinity which may be useful as recruiting
elements for PROTACs. It is also conceivable that these new
molecules are able to induce the degradation of additional neo-
substrates or indeed inhibit the binding of natural substrates to
CRBN, perhaps providing a useful tool to discover currently
unknown substrates of CRBN. Finally, we hope this efficient
synthetic method will prove useful to those engaged in the exciting
field of targeted protein degradation.
employee of Arvinas, LLC. Other authors declare no conflict
of interests.
Footnotes
† Alternatively, tert-Butyl 2,6-dioxopiperidin-3-ylcarbamate is
commercially available.
‡ Phthalic acid heated to 150°C in TFE for 2 hours under
microwave conditions is converted into the anhydride.
Keywords: Protein Degradation • Immunomodulatory Drugs •
Imides • Condensation Reactions • Cereblon
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
G.M. Burslem,* P. Ottis, S. Jaime-
Figueroa, A. Morgan, P.M. Cromm, M.
Toure and C.M. Crews*
Page No. – Page No.
Efficient Synthesis of
Immunomodulatory Drug Analogues
Enables Exploration of Structure
Degradation Relationships
Herein we disclose a rapid and efficient synthesis of immunomodulatory drugs
(ImiDs). This approach enabled the preparation of a wide variety of analogues with
good functional group tolerance. Furthermore, we explore the binding of these
analogues to the E3 ligase Cereblon (CRBN) biophysically as well as characterise
their cellular activity, revealing further details about the structure degradation
relationships for molecules of this type.
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