Development of Rapid and Facile Solid-Phase Synthesis of Protacs Via A Variety of Binding Styles

Research Article
ChemistryOpen doi.org/10.1002/open.202200131
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Development of Rapid and Facile Solid-Phase Synthesis of

PROTACs via a Variety of Binding Styles
Hanqiao Xu+,[a, b] Takashi Kurohara+,[a] Reina Takano,[a, b] Hidetomo Yokoo,[a, c]
Norihito Shibata,[a] Nobumichi Ohoka,[a] Takao Inoue,[a] Mikihiko Naito,[d] and
Yosuke Demizu*[a, b]
Optimizing linker design is important for ensuring efficient syntheses. Herein, a solid-phase approach for convenient
degradation activity of proteolysis-targeting chimeras (PRO- PROTAC synthesis is presented. We designed azide intermedi-
TACs). Therefore, developing a straightforward synthetic ap- ates with different linker lengths to which the E3 ligand,
proach that combines the protein-of-interest ligand (POI ligand) pomalidomide, is attached and performed facile PROTACs
and the ligand for E3 ubiquitin ligase (E3 ligand) in various synthesis by forming triazole, amide, and urea bonds from the
binding styles through a linker is essential for rapid PROTAC intermediates.
Introduction apoptosis protein ligand (LCL161) have been widely used as E3

ligands.[3] Alkyl and PEG chains are commonly used to link the
Protein knockdown technology has attracted significant atten- POI and E3 ligands.[4] The mechanism of PROTACs is to recruit
tion as a new approach in drug discovery. Proteolysis-targeting E3 ligase to the POI, which promotes poly-ubiquitination of the
chimeras (PROTACs) and specific and nongenetic inhibitors of POI and subsequent proteasomal degradation. Since the first
apoptosis protein-dependent protein erasers (SNIPERs) are discovery of PROTACs,[5] numerous proteins have been targeted
representative chimeric compounds that facilitate protein in drug discovery research. Therefore, PROTACs undoubtedly
degradation by hijacking the ubiquitin-proteasome system became a new modality in the pharmaceutical industry.
(Figure 1a).[1,2] These chimeric compounds are constructed from Discovering POI ligands that bind to target proteins with
three components: (a) a protein-of-interest ligand (POI ligand); appropriate affinity is essential for improving the protein
(b) a ligand for E3 ubiquitin ligase (E3 ligand); and (c) a linker degradation activity of PROTACs. Moreover, optimizing the
that combines the POI and E3 ligands. Generally, small length and structure of the linkers ensures efficient ubiquitina-
molecular ligands that bind to the target protein are used as tion by separating the two ligands by an appropriate distance.
POI ligands. The cereblon ligand (thalidomide and pomalido- In contrast to the ongoing discovery and optimization of POI
mide), von Hippel-Lindau ligand (VH032), and inhibitor of ligands and linkers, respectively, there are only a few E3 ligands
that are commonly used for PROTACs, and thalidomide-type
[a] H. Xu,+ Dr. T. Kurohara,+ R. Takano, Dr. H. Yokoo, Dr. N. Shibata, ligands (e. g. pomalidomide) are one of the more widely used
Dr. N. Ohoka, Dr. T. Inoue, Dr. Y. Demizu building blocks for PROTAC development because they have a
National Institute of Health Sciences smaller molecular weight and are easy to synthesize when
3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501 (Japan)
E-mail: demizu@nihs.go.jp compared with other E3 ligands. Thus, screening for POI ligands
Homepage: https://www.nihs.go.jp/doc/ and linkers is often investigated as a priority. However, these
[b] H. Xu,+ R. Takano, Dr. Y. Demizu fragments are highly polar, while pomalidomide is less polar,
Graduate School of Medical Life Science
Yokohama City University making it difficult to handle during liquid-phase synthesis.
1-7-29 Yokohama, Kanagawa, 230-0045 (Japan) Furthermore, PROTACs must be isolated in high purity after
[c] Dr. H. Yokoo synthesis because they are used in biological experiments.
Medical Chemistry
Graduate School of Medical Science These are some of the factors delaying the development of
Kyoto Prefectural University of Medicine PROTACs.
Kyoto 606-0823 (Japan) We focused on the concept that PROTACs can be rapidly
[d] Prof. M. Naito
Laboratory of Targeted Protein Degradation and easily synthesized by solid-phase organic synthesis
Graduate School of Pharmaceutical Sciences (SPOS).[6] SPOS is a powerful synthetic tool used widely in
The University of Tokyo combinatorial and high-throughput chemistry.[7] For drug
Tokyo 113-0033 (Japan)
discovery research, SPOS is used for constructing drug-like
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
libraries from solid-phase parallel syntheses.[8,9] The first SPOS-
https://doi.org/10.1002/open.202200131 based PROTAC synthesis has been reported by S. Krajcovicova
© 2022 The Authors. Published by Wiley-VCH GmbH. This is an open access and co-workers, in which a POI ligand was coupled with E3
article under the terms of the Creative Commons Attribution Non-Com- ligase by alkylation of the carbonyl α-position (Figure 1b).[6]
mercial NoDerivs License, which permits use and distribution in any med-
ium, provided the original work is properly cited, the use is non-commercial Further construction of PROTACs requires various conjugations
and no modifications or adaptations are made. such as O-/N-alkylation,[10] amide formation,[11] triazole
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Research Article
Therefore, this strategy is suitable for facile synthesis of

PROTACs targeting different proteins, and PROTAC synthesis
with varying lengths of the linker and POI ligands was also
investigated.
Results and Discussion
We initially synthesized PROTACs targeting hematopoietic

prostaglandin D synthase (H-PGDS) using 3-azidopropylamine
as a three-carbon linker and TFC-007 as the POI ligand, an H-
PGDS inhibitor. This PROTAC(H-PGDS) was recently reported by
our group, and the results suggested that a shorter linker is
ideal for its activity, which exemplifies the importance of
diversifying the linker structure to improve degradation
activity.[14,15] Initially, we used an aminomethyl polystyrene resin
(4, 2.0–3.0 mmol g 1, 50 mg) to acylate with 4-(4-formyl-3-meth-
oxyphenoxy)butanoic acid (5) following a known method, and
3-azidopropylamine was introduced by reductive amination to
afford resin 6.[6] Progress of the reaction was monitored by the
chloranil test.[16] After condensing the pomalidomide derivative
(7) onto resin 6, the desired intermediate resin 1 with the azide
linker was obtained by cleavage from the resin, followed by LC-
MS analysis.
Next, we performed copper(I)-catalyzed azide-alkyne cyclo-
addition (CuAAC), amide formation, and urea formation reac-
tions from the azide intermediate of resin 1. Azide-alkyne
cyclization was carried out between the azide intermediate and
the TFC-007-alkyne derivative (8) by two cycles of coupling
reaction at room temperature for 24 h in the presence of CuI
(Scheme 1b). After cleavage from the resin and purification by
RP-HPLC, PROTAC 1 was isolated with 97 % purity. The azide
group of intermediate 1 on the resin was converted to the
amino group (2) by the Staudinger reaction and followingly
applied to amide-type PROTAC synthesis (Scheme 1b).[17] Ac-
cordingly, after reducing the azide group and subsequent
Figure 1. (a) Protein degradation mechanism of PROTACs. (b) A reported condensation with TFC-007-CH2CO2H (9), the amide-type PRO-
solid-phase PROTAC synthesis by alkylation. (c) Solid-phase PROTAC syn- TAC 2 was obtained with > 99 % purity by RP-HPLC purification.
thesis by various conjugation reactions (this work).
Urea formation between resin 2 and compound 10 using 4-
nitrophenyl chloroformate was also achieved to obtain PROTAC
3 with > 95 % purity. For the construction of PROTACs by
formation,[12] and ester formations.[13] Hence, in this study, we amidation, it is necessary to assume the reverse type of amide
aimed to demonstrate the facile synthesis of PROTACs with formation, in which the amino group of the linker and the
various linker and ligand conjugations. Synthesizing PROTACs carboxy group of the POI ligand are swapped. Thus, another
with diverse conjugations requires the design of a common E3 synthetic route was designed using allyl 3-aminopropanoate
ligand bound to a linker intermediate. We focused on instead of 3-azidopropylamine for the carboxylic acid linker
converting an azide group into a variety of motifs without any synthesis (Scheme 1c). Intermediate resin 3 was synthesized by
protection. Thus, we designed the intermediate azide-resin 1 condensation of compound 5 to resin 4, reductive amination
with the E3 ligand already bonded to the alkyl linker (Figure 1c). with allyl 3-aminopropanoate, condensation with compound 7,
For divergent synthesis, in addition to resin 1, we designed and subsequent allyl deprotection by phenylsilane in the
amino-resin 2, which can be synthesized by reduction of resin 1 presence of Pd(OAc)2 as the catalyst. After condensation with
and carboxylic acid resin 3. These resins 1–3 were reacted with compound 10, subsequent cleavage from the resin and RP-
an alkyne (A), a carboxylic acid (B), and amines (C, D) of POI HPLC purification yielded the reverse amide-type PROTAC 4
ligands to obtain amide-, triazole-, and urea-based PROTACs. with 97 % purity.
Using this synthetic strategy, the E3 ligand pomalidomide and Next, we synthesized the amide-type PROTACs with differ-
the linker were constructed during the early stages of the ent linker lengths. Because long linkers are not suitable for
synthesis, and the POI ligand was introduced at a later stage. PROTACs(H-PGDS),[15] we chose dBET1[18] and dBET6[19] as a
Research Article
Scheme 1. Solid-phase synthesis of PROTACs(H-PGDS). (a) Synthesis of intermediate resin 1. (b) Synthesis of PROTACs 1–3 from resin 1. (c) Synthesis of
PROTAC 4 using resin 3. Abbreviations: DIC: N,N’-diisopropylcarbodiimide; HOBt: 1-hydroxybenzotriazole; HBTU: 1-[bis(dimethylamino)methylene]-1H-
benzotriazolium 3-oxide hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; TFA: trifluoroacetic acid.
synthetic target. These are typical PROTACs with alkyl linkers amine were synthesized separately and used as starting linkers
that contain JQ1 as a POI ligand and degrade the target protein, (Scheme S4, Supporting Information). The synthetic route was
bromodomain-containing 4 (BRD4).[20] A number of PROTACs the same as that used for PROTAC 2, with each linker attached
targeting BRD4 have been reported for cancer therapy.[21] Most to resin 4 to obtain resins 6, 11, and 12. Subsequent
of them contain an alkyl linker,[18,19,22] while others are based on condensation with compound 7 gave the azide intermediates 1,
a PEG linker,[23] a photoswitchable azobenzene type,[24] or 13, and 14, which upon further reduction afforded resins 2, 15,
dihydropyrazine[25] formed by cyclization of trans-cyclo-octene and 16. Finally, (+)-JQ1-CO2H (17) was coupled to the resins to
with tetrazine. In the reported dBET1 and dBET6, thalidomide obtain the target PROTACs 5–7 with > 99 % purity.
was used as the E3 ligand, but the C O bond of thalidomide is We have successfully constructed azide-alkyne cycloaddi-
possibly more unstable in buffer (pH 7.4) and human plasma tions and amide bonds, which are used widely in synthesizing
than the C N bond of pomalidomide.[26] Therefore, we decided PROTACs, with efficient pathways and reaction conditions
to synthesize the pomalidomide-type dBET (PROTACs 5–7, suitable for solid-phase synthesis. Thus, the rapid and straight-
Scheme 2). For the synthesis of PROTACs 5–7, in addition to 3- forward synthesis of PROTACs by the solid-phase method
azidopropylamine, 4-azidobutan-1-amine, and 8-azidooctan-1- improves the convenience of complicated PROTACs syntheses
Research Article
Scheme 2. Solid-phase synthesis of PROTACs(BRD4) 5–7. Abbreviation: THPP: tris(hydroxypropyl)phosphine.
by the liquid-phase method. In the reported solid-phase

PROTAC synthesis,[6] the E3 ligand is bound to the Fmoc-
protected amine, followed by Fmoc deprotection and finally the
introduction of the POI ligand. In contrast, our method uses the
azide moiety, which has high reaction tolerance as the binding
motif for POI ligand linkage, and we succeeded in diversifying
the linker and omitting the protection and deprotection steps.
Finally, we evaluated the degradation activity of the
synthesized PROTACs against their respective target proteins by
western blotting. The degradation activity of PROTACs 1, 2, and
4 against H-PGDS was evaluated in KU812 cells. PROTAC 1 with
the triazole moiety was found to have the highest degradation
activity against H-PGDS and comparable to the reported
PROTAC(HPGDS)-1 (Figure 2a). In contrast, PROTAC 4, which
has an inverted amide bond, showed the lowest degradation
activity. The degradation activity of PROTACs 5–7 against BRD4
Figure 2. (a) H-PGDS protein reduction activity of PROTACs 1, 2, and 4 in
was evaluated in MV4-11 cells, and PROTAC 7 with the longest KU812 cells. (b) BRD4 protein reduction activity of PROTACs 5–7 in MV4-
linker showed the highest activity, which was higher than the 11 cells.
reported dBET1 activities (Figures 2b and S1).
Experimental Section
Conclusion
General Information
In summary, we have rapidly and easily synthesized PROTACs
All chemicals were purchased from Sigma-Aldrich Co. LLC, Kanto
by a solid-phase method using various conjugation reactions.
Chemicals Co. Inc., Tokyo Chemical Industry Co. Ltd., Wako Pure
Triazole, amide, urea, and reverse amide formation reactions Chemical Industries Ltd., and were used without further purifica-
were exploited to synthesize PROTACs (H-PGDS). We have also tion. Reactions were followed by thin-layer chromatography (TLC)
synthesized pomalidomide derivatives of dBET as PROTACs with (60 F254, Merck), and spots were visualized by UV irradiation with a
different alkyl-linker lengths and have shown that they exhibit handheld UV lamp (254/365 nm) (UVP) and iodine vapor or
potent degradation activity. The solid-phase PROTAC synthetic ninhydrin reagent. Silica gel for column chromatography was Kanto
Chemical 60 N (spherical, neutral), NH silica gel (Chromatrex NH-
method presented in this study should facilitate the rapid DM1020, Fuji Silicia), or packed columns for medium pressure
development of PROTACs targeting various proteins. column chromatography (Hi-Flash column / Inject column Yama-
zen). Resin: Aminomethyl polystyrene resin (50 mg, loading
2.5 mmol g 1). Reagent for acetaldehyde/chloranil tests: 2 %
Research Article
acetaldehyde in N,N-dimethylformamide (DMF), 2 % chloranil in the resin was suspended in a cleavage cocktail (50 % trifluoroacetic
DMF. 1H and 13C NMR spectra were measured on an ECZ 600R acid (TFA) and 50 % CH2Cl2) at room temperature for 1 h. The
spectrometer (JEOL) using deuterated solvents. Chemical shift cleavage cocktail with combined wash was evaporated under a
values (ppm) were corrected for residual solvent signals as internal stream of nitrogen, the crude products were dissolved in MeOH
standards [DMSO-d6: 2.50 for 1H NMR, 39.5 for 13C NMR; CD3OD: 3.30 (3 mL) and purified by HPLC (gradient: 40–80 % MeCN-H2O, 30 min)
for 1H NMR, 49.0 for 13C NMR; CDCl3: 7.26 for 1H NMR, 77.2 for to give PROTAC 1 (2.4 mg) in 1 % yield.
13
C NMR]. The splitting modes of the signals are as follows (singlet
(s), doublet (d), triplet (t), quartet (q), double of doublets (dd), Procedure for the synthesis of PROTAC 2 by amidation: Resin 2
multiplet (m), broad (br)). High-resolution mass spectrometry (50 mg, loading 2.5 mmol g 1) was swollen in CH2Cl2 (2 mL) for
(HRMS) was measured by electrospray ionization using Shimadzu 30 min, and washed with DMF (3 × 2 mL). The mixture of compound
IT-TOF MS (Shimadzu). 9 (204 mg, 0.375 mmol), HOBt (124 mg, 0.375 mmol), HBTU
(143 mg, 0.375 mmol) and N,N-diisopropylethylamine (97 mg,
0.75 mmol) in DMF was added to the resin and shaken overnight at
Solid-Phase Organic Synthesis room temperature, followed by washing with DMF (3 × 2 mL). The
resin was suspended in a cleavage cocktail (50 % TFA and 50 %
CH2Cl2) at room temperature for 1 h. The cleavage cocktail with
Procedure for loading of the amide linker and combined wash was evaporated under a stream of nitrogen, the
3-azidopropylamine onto a resin (synthesis of resin 6) crude products were dissolved in MeOH (3 mL) and purified by
Loading of amide linker: Aminomethyl polystyrene resin (50 mg, HPLC (gradient: 10–90 % MeCN-H2O containing 0.1 % TFA, 30 min)
loading 2.5 mmol g 1) was swollen in CH2Cl2 (2 mL) for 30 min, to give PROTAC 2 (2.1 mg) in 1 % yield.
washed with DMF (3 × 2 mL), neutralized in DMF/piperidine (5 : 1, Procedure for the synthesis of PROTAC 3 by urea formation: Resin
2 mL) for 30 min and washed with DMF (3 × 2 mL). Backbone amide 2 (50 mg, loading 2.5 mmol g 1) was swollen in CH2Cl2 (2 mL) for
linker of 4-(4-formyl-3-methoxyphenoxy)butanoic acid (90 mg, 30 min, and washed with DMF (3 × 2 mL). 4-Nitrophenyl chlorofor-
0.375 mmol), 1-hydroxybenzotriazole (HOBt, 51 mg, 0.375 mmol) mate was dissolve in THF (1 mL) and stirred at 40 °C for 30 min
were dissolved in DMF/CH2Cl2 (1 : 1, 2 mL, v/v) and N,N’-diisopropyl- and then added to the resin with N,N-diisopropylethylamine
carbodiimide (DIC, 59 μL, 0.375 mmol) was added. The resulting (97 mg, 0.75 mmol) and stirred for 24 h at room temperature. The
solution was added to resin. The reaction slurry was shaken at mixture of compound 10 (182 mg, 0.375 mmol), N,N-diisopropyle-
room temperature overnight, followed by wash with DMF (3 × 2 mL) thylamine (97 mg, 0.75 mmol) and 4-dimethylaminopyridine
and CH2Cl2 (3 × 2 mL). Acetaldehyde/Chloranil test confirmed the (DMAP, 10 mg, 0.075 mmol) in THF/DMF (1 mL) was added to the
absence of amino groups. resin and stirred for 16 h at room temperature, followed by washing
Loading of 3-azidopropylamine: The resin intermediate was swollen with DMF (3 × 2 mL). The resin was suspended in a cleavage cocktail
in CH2Cl2 (2 mL) for 30 min, and washed with DMF (3 × 2 mL). The (50 % TFA and 50 % CH2Cl2) at room temperature for 1 h. The
solution of 3-azidopropylamine (38 mg, 0.375 mmol) in DMF/AcOH cleavage cocktail with combined wash was evaporated under a
(10 : 1, 2 mL, v/v) was added to resin and shaken overnight at room stream of nitrogen, the crude products were dissolved in MeOH
temperature. NaBH(OAc)3 (80 mg, 0.375 mmol) in DMF/AcOH (20 : 1, (3 mL) and purified by HPLC (gradient: 40–80 % MeCN-H2O, 30 min)
2 mL, v/v) was added to the reaction mixture for 4 h, followed by to give PROTAC 3 (3.3 mg) in 1 % yield.
washing with DMF (3 × 2 mL). Acetaldehyde/Chloranil test con- Procedure for the synthesis of carboxylic acid resin 3: Resin 3 was
firmed the absence of amino groups. synthesized same manner as resin 1 via compound 5 condensation
Procedure for loading of pomalidomide onto a resin (synthesis of to the resin 4, reductive amination, compound 7 condensation, and
resin 1): Resin 6 (50 mg, loading 2.5 mmol g 1) was swollen in following allyl deprotection by Pd(OAc)2 catalyst with phenylsilane.
CH2Cl2 (2 mL) for 30 min, and washed with DMF (3 × 2 mL). The The procedure for allyl deprotection is as follows; Resin after the
mixture of compound 7 (124 mg, 0.375 mmol), HOBt (61 mg, compound 7 condensation (50 mg, loading 2.5 mmol g 1) was
0.375 mmol), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium swollen in CH2Cl2 (2 mL) for 30 min, and washed with DMF (3 ×
3-oxide hexafluorophosphate (HBTU, 143 mg, 0.375 mmol) and N,N- 2 mL). The mixture of palladium(II) acetate (5.6 mg, 0.025 mmol)
diisopropylethylamine (DIPEA, 97 mg, 0.75 mmol) in DMF was and phenylsilane (270.5 mg, 2.5 mmol) in CH2Cl2 was added to the
added to the resin and shaken overnight at room temperature, resin and shaken overnight at room temperature, followed by
followed by washing with DMF (3 × 2 mL). washing with DMF (3 × 2 mL) for 2 times.
Procedure for reduction of the azide group of resin 1 (synthesis Procedure for the synthesis of PROTAC 4 by amidation: Resin 3
of resin 2): Resin 1 (50 mg, loading 2.5 mmol g 1) was swollen in (50 mg, loading 2.5 mmol g 1) was swollen in CH2Cl2 (2 mL) for
CH2Cl2 (2 mL) for 30 min, and washed with DMF (3 × 2 mL). 30 min, and washed with DMF (3 × 2 mL). The mixture of compound
Tris(hydroxypropyl)phosphine (THPP, 78 mg, 0.375 mmol) was dis- 10 (182.5 mg, 0.375 mmol), HOBt (124 mg, 0.375 mmol), HBTU
solved in water/DMF (1 : 9, 2 mL, v/v) and added to the resin shaken (143 mg, 0.375 mmol) and N,N-diisopropylethylamine (97 mg,
overnight at room temperature, followed by washing with DMF (3 × 0.75 mmol) in DMF was added to the resin and shaken overnight at
2 mL). room temperature, followed by washing with DMF (3 × 2 mL). The
resin was suspended in a cleavage cocktail (50 % TFA and 50 %
The resin 15 and 16 were synthesized from resin 4 in the same CH2Cl2) at room temperature for 1 h. The cleavage cocktail with
manner as resin 2, using 4-azidobutan-1-amine for resin 15 and 8- combined wash was evaporated under a stream of nitrogen, the
azidooctan-1-amine for resin 16 instead of 3-azidopropylamine. crude products were dissolved in MeOH (3 mL) and purified by
HPLC (gradient: 30–70 % MeCN-H2O, 30 min) to give PROTAC 4
Procedure for the synthesis of PROTAC 1 by CuAAC: Resin 1
(1.2 mg) in 1 % yield.
(50 mg, loading 2.5 mmol g 1) was swollen in CH2Cl2 (2 mL) for
30 min, and washed with DMF (3 × 2 mL). The mixture of 8 (202 mg, Procedure for the synthesis of PROTACs 5–7: The PROTACs 5–7
0.375 mmol), CuI (24 mg, 0.125 mmol) and N,N-diisopropylethyl- were synthesized in the same manner as PROTAC 2 synthesis by
amine (97 mg, 0.75 mmol) in DMF was added to the resin and using compound 17 instead of compound 7.
shaken for 24 h at room temperature, followed by washing with
DMF (3 × 2 mL). After performing the above coupling reaction twice,
Research Article
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PROTAC 5 (9.3 mg) in 10 % yield. [6] S. Krajcovicova, R. Jorda, D. Hendrychova, V. Krystof, M. Soural, Chem.
Commun. 2019, 55, 929–932.
PROTAC 6: The crude product was dissolved in MeOH (3 mL) and [7] N. Cankařová, E. Schütznerová, V. Krchňák, Chem. Rev. 2019, 119,
purified by HPLC (gradient: 10–90 % MeCN-H2O, 30 min) to give 12089–12207.
PROTAC 6 (1.5 mg) in 2 % yield. [8] T. Lee, Y. D. Gong, Molecules 2012, 17, 5467–5496.
[9] A. Abdildinova, Y. D. Gong, ACS Comb. Sci. 2018, 20, 309–329.
PROTAC 7: The crude product was dissolved in MeOH (3 mL) and [10] D. K. Brownsey, B. C. Rowley, E. Gorobets, B. S. Gelfand, D. J. Derksen,
purified by HPLC (gradient: 40–80 % MeCN-H2O, 30 min) to give Chem. Sci. 2021, 12, 4519–4525.
[11] X. Qiu, N. Sun, Y. Kong, Y. Li, X. Yang, B. Jiang, Org. Lett. 2019, 21, 3838–
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D. Mohl, C. Sastri, J. R. Lipford, V. J. Cee, J. Med. Chem. 2018, 61, 453–
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Development of Rapid and Facile Solid-Phase Synthesis of Protacs Via A Variety of Binding Styles

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Development of Rapid and Facile Solid-Phase Synthesis of Protacs Via A Variety of Binding Styles

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Research Article

Development of Rapid and Facile Solid-Phase Synthesis of

Introduction apoptosis protein ligand (LCL161) have been widely used as E3

Therefore, this strategy is suitable for facile synthesis of

Results and Discussion

We initially synthesized PROTACs targeting hematopoietic

Scheme 2. Solid-phase synthesis of PROTACs(BRD4) 5–7. Abbreviation: THPP: tris(hydroxypropyl)phosphine.

by the liquid-phase method. In the reported solid-phase

[1] M. J. Bond, C. M. Crews, RSC Chem. Biol. 2021, 2, 725–742.

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