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. 2023 Jan 6;18(1):25–33. doi: 10.1021/acschembio.2c00797

Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach

Qiuxia Chen †, Chuan Liu †, Wei Wang †, Xiaoyun Meng †, Xuemin Cheng †, Xianyang Li †, Longying Cai †, Linfu Luo †, Xu He †, Huan Qu †, Jing Luo †, Hong Wei †, Sen Gao ‡, Guansai Liu ‡, Jinqiao Wan ‡, David I Israel §, Jin Li §, Dengfeng Dou †,*
PMCID: PMC9872815  PMID: 36606710

Abstract

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The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.

Introduction

The down-regulation of protein activity or protein levels is a common mechanism of disease treatment. For proteins that have multiple functions,1,2 high homology within family members,3,4 or mutations associated with disease,5,6 inhibition of protein function with small molecule drugs can be an ineffective therapeutic strategy. Alternatively, genetic or chemical protein knockdown/knockout approaches including RNAi,7,8 CRISPR/Cas9,9,10 and targeted protein degradation (TPD)11,12 are rapidly advancing. Several clinically important monomeric protein degraders or molecular glues were discovered by serendipity.13 The systematic discovery and development of protein degraders, such as proteolysis targeting chimeras (PROTACs), is of high interest to the pharmaceutical industry.

PROTACs hijack the intracellular E3 ligase and the ubiquitin–proteasome machinery and induce polyubiquitination and subsequent proteasome-mediated degradation of the target protein.14 A heterobifunctional PROTAC degrader consists of three components: a protein of interest (POI) binder, an E3 ligase binder, and a linker tethering the two. Compared with inhibitors, PROTACs have several key advantages: (1) only binding to a POI is required, which overcomes potential active site mutation issues;11,15−17 (2) a less demanding binding affinity requirement to the POI minimizes dose-limiting toxicity;18 (3) their catalytic nature requires a lower dose and may achieve a long-lasting effect;19−24 (4) they are more selective than inhibitors because of additional POI-E3 protein–protein interaction or E3 ligase tissue/cell distribution differentiation.21,25−32 PROTAC is now a proven technology to target undruggable target classes such as protein–protein interaction targets and scaffold proteins. With multiple programs entering and progressing in clinical trials,11,12 the efficient discovery, optimization, and development of PROTACs is of high value.

The majority of PROTAC discovery and development programs use known POI and E3 ligase binders and optimize the linker or entire molecule to achieve the required degradation potency, selectivity, and other properties. The SAR of PROTACs heavily relies on cell-based assays like Western Blot or HiBit, which is the ultimate result of PROTAC penetration into the cell, ternary complex formation, ubiquitination, and proteasome-mediated degradation. However, reliance on these assays for SAR is frequently found to be time-consuming and difficult to know which step causes PROTAC activity change. There are multiple factors contributing to this: (1) PROTAC solubility and permeability variation, (2) effectiveness of the ternary complex formation and ubiquitination rate, and (3) POI degradation by proteasome and the release/recycling of the PROTAC. Among these factors, ternary complex formation, with a proper orientation of the E3 ligase with the POI to allow for efficient ubiquitin transfer, is perhaps the most essential step for improving PROTAC potency and selectivity. Biochemical ternary complex assays such as FRET or AlphaLISA are commonly used. However, these assays are not always predictive of subsequent ubiquitination and require significant amounts of protein if a large number of PROTACs are evaluated. Therefore, a more effective method for ternary complex formation is desirable, particularly in the early steps of the PROTAC discovery process.

DNA-encoded library (DEL) is a powerful technology for parallel synthesis and screening by affinity selection for millions or billions of compounds. The DEL affinity selection process perfectly matches affinity-based PROTAC discovery needs,33 as evidenced by several recent reports of the discovery of POI binders with PROTAC applications.34,35 Considering the three components of PROTACs as the three components of a DEL library, encoding all the POI binders, linkers, and E3 ligase binders with DNA barcodes allows for the synthesis of all desired PROTACs in a very cost-effective fashion. The principle of the affinity selection of DELs is to allow simultaneous binding of DEL ligands to a target protein. Unbound library members are removed, and the amount of each library compound bound to the protein is determined by DNA sequence analysis. For a PROTAC application, we hypothesize that the DEL selection signals will be influenced by the binding of ligands to both the E3 ligase and the POI. One or the other of the proteins can exhibit a positive or negative cooperative effect, as measured by a DNA sequence count of bound library compounds. Linkers play an important role in a PROTAC molecule since shorter linkers can cause a protein binding conflict, whereas longer linkers need to pay an entropy penalty, and linker rigidity and attachment point to the ligands can greatly affect the complex formation. Because of the known importance of linkers on PROTAC binding and activity, we expect to observe different levels of PROTAC enrichment for the different linkers used for each POI ligand/E3 ligand pair in the DEL library. We hypothesized that by encoding a variety of linkers as a part of library design and synthesis, these differences (as measured by DNA sequence count) directly reflect relative ternary complex binding cooperativity. This approach also eliminates the bias due to PROTAC solubility (DNA tags make all the compounds hydrophilic), and this shotgun approach can evaluate millions of compounds simultaneously and significantly reduce the time and cost.

We chose trifunctional linkers (as shown in Figure 1A) in the design of the PROTAC DEL in order to minimize the potential interference of DNA with the POI and E3 ligase ligands. Several trivalent PROTACs targeting dual proteins using the same E3 ligase have been reported, which suggests that variations of the linker can be tolerated in multiple protein–protein interactions.36−38 If the E3 ligase ligand has multiple known extension points that do not significantly affect its binding, a PROTAC DEL can be designed with the DNA linker attached to one end of the E3 ligase ligand and various linkers and POI binders attaching from the other end.39 We used this former DEL design as a demonstration of the general strategy for DEL-based PROTAC synthesis and ligand discovery.

Figure 1.

Figure 1

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(A) The PROTAC DEL is constructed with trivalent linkers and a fixed CRBN ligand (thalidomide). The Control DEL is constructed the same as the PROTAC DEL, except there is an amine in place of thalidomide. (B) Four selection samples are in the Selection Plan in order to identify molecules that simultaneously bind to BRD4 and CRBN/DDB1. Detailed screening scheme of Sample 1 and Sample 3 is shown.

Results and Discussion

PROTAC DEL and Control DEL Construction

We tested the above hypotheses by designing and synthesizing PROTAC and control libraries as shown in Figure 1A. Specifically, in DEL1323–1 and DEL1323–3, the potential POI binders are the combination of 757 boronates (R3) and 519 carboxylic acids (R2). There are also 16 variable linkers (R1) attached to DNAs, and thalidomide is used as the CRBN binder (DEL1323–1), or null (DEL1323–3) is used as the control. We also synthesized 16 dBET1-like DNA conjugates (same linkers and CRBN warhead as DEL1323–1, but R2-R3 replaced with JQ1) as positive controls.

DEL Selection and DNA Sequencing

For the DEL selection, we chose BRD4 as the POI. BRD4 has been intensively studied as a model target for PROTAC-mediated degradation40−42 and is still considered as a potential cancer target despite its selectivity challenges over BRD2 and BRD3.43−45 Many CRBN-based BRD4 PROTACs have been reported, where the most cited BRD4 PROTACs for CRBN are dBETs.40,41 In our experiment, we chose CRBN as the E3 ligase and used dBET1 as the reference PROTAC to evaluate the effectiveness of our approach. PROTAC DEL1323–1 and Control DEL1323–3 (Figure 1), along with 16 dBET1-like DNA conjugates, were pooled for affinity selection. We immobilized either BRD4 or CRBN in different selection rounds by using GST-tagged BRD4 and His-tagged CRBN/DDB1. We conducted DEL selections by incubation of libraries with His-tagged CRBN/DDB1 and GST-tagged BRD4 simultaneously or for comparison incubation with CRBN/DDB1 or BRD4 alone. The selection output was PCR amplified, sequenced, and processed for analysis (selection details are illustrated in Figure 1B).

Selection Result Analysis

After data deconvolution, the remaining compounds in each selection sample are visualized in cubic plots, with the sizes of the bubbles proportional to sequence counts (Figure 2). The 16 dBET1-like PROTAC conjugates (in red oval, Figure 2A) were readily identified in samples containing CRBN and BRD4, thereby validating the selection conditions. The corresponding JQ1–linker conjugates (in red oval, Figure 2B) were also identified with moderate signals. This is likely because of the strong binding of JQ1 to BRD4 and unbiased capture in the second round of selection. For PROTAC DEL1323–1, many PROTAC molecules were significantly enriched in Sample 1 and moderately enriched in Sample 3. The dual protein incubation signal enhancement should be due to the cooperativity caused by PROTACs. Furthermore, differences in copy counts along the R1 axis for each compound represent linker effects on binding of the bifunctional library compound to CRBN and BRD4, which is suggestive of cooperativity. Finally, for Sample 1, the signals in DEL1323–1 were stronger than DEL1323–3, which provided another line of evidence of cooperativity. The signals in DEL1323–3 (R1 = 11, phenylalanine derivatives, Figure 3A) were identified as background noise.

Figure 2.

Figure 2

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Cubic view of DEL selection results. The proteins used in Samples 1–4 (S1–S4) are shown below each cube. Each library compound has a unique R1-R2-R3 coordinate, with the corresponding bubble size reflecting DNA sequence counts. The R1 dimension represents the 16 encoded trifunctional linkers, whereas the R2 and R3 dimensions represent 519 carboxylic acids and 757 boronates, respectively. The 16 JQ1-containing DNA conjugates are shown along the R1 axis, at the upper left of each cube, and are highlighted by the red oval. (A) PROTAC DEL1323–1 comparison for Samples 1–4. (B) Control DEL1323–3 selection comparison for Samples 1–4.

Figure 3.

Figure 3

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(A) Representative features and selected PROTAC structures (sequence counts in Sample 1–4 are indicated). (B) Sequence counts and their comparison for representative PROTACs and their null controls. (C) Ternary complex formation assay for BRD4 and CRBN/DDB1 by PROTAC compounds. Data is presented as mean ± SD (n = 3).

Resynthesis and Validation

The correlation of structure, sequence count, and ternary complex formation was better understood by selecting nine representative PROTACs from three line features intercepted at DEL1323–1–13–311–348 (R1 = 13, R2 = 311, R3 = 348, where each number represents a different trifunctional linker, carboxylic acid building block, or boronate building block, respectively) for resynthesis without DNA. Resynthesized compounds were characterized in a ternary complex formation assay (Figure 3A,C). The sequence counts of these nine PROTACs in Sample 1 and Sample 3 and the sequence counts of the corresponding compounds in DEL1323–3 in Sample 1, are summarized in the table in Figure 3B, where the S1/S3 ratio reflects the cooperativity of PROTAC molecules binding to BRD4 in the presence, versus the absence, of CRBN/DDB1, and the DEL1323–1/DEL1323–3 ratio reflects cooperativity provided by binding to CRBN via the thalidomide moiety. A careful comparison of ternary complex formation to sequence counts of PROTACs in Sample 1, S1/S3, DEL1323–1/DEL1323–3, shows good consensus in the rank ordering of complex stability and sequence counts. For the two best PROTACs, Cpd 1 and Cpd 5 have higher and broader curves in the ternary complex assay (Figure 3C); positive cooperativity was also observed with α > 1 by comparing the potency in the absence and presence of the other protein (Table S1).

SAR Analysis

Linker variation in R1 (Cpd 1–4) suggested that (1) 5-methylene linker (Cpd 1) is optimal for flexible linkers, (2) the rigidity of linker (Cpd 3) is less favorable, and (3) NH to N-alkyl replacement is unfavorable (Cpd 4). For R2 variation (Cpd 1, 5–7), Cpd 1 and Cpd 5, which have both the highest sequence counts and PROTAC/null ratios (DEL1323–1/DEL1323–3), form much more stable ternary complexes than Cpd 6 and Cpd 7 (1.5 orders of magnitude weaker), which indicates the importance of R2 direct interaction or a combined interaction of R2-R3 with BRD4. Finally, comparison of the three compounds (Cpd 1, 8–9) with R3 variation identified alternative R3 = 612 with H replacement on 1-methylpyridone. The R3 with phenyl insertion plus pyridone saturation (Cpd 9) had significantly lower sequence counts and ternary complex stability. Taken together, the SAR of the three orthogonal lines supports our hypothesis that DEL selection sequence counts reflect the relative ternary complex recruitment ability of the DNA-encoded PROTAC molecule. The dual-protein selection/single-protein selection and PROTAC/null ratios we observed provide additional support of this hypothesis. It has been reported that negative cooperativity has been proved to effectively degrade cellular target proteins,46,47 and our selection strategy provides a useful strategy to differentiate the positive/non/negative cooperative effect between POI–PROTAC–E3. One would expect the equivalent signal/ratio for Sample 1 and Sample 3 in a noncooperative case and higher signal/ratio in Sample 3 in a negative cooperative case.

Degradation and MOA Studies

We evaluated BRD4 degradation of these PROTACs in the MV4;11 cell line. We chose this cell line for BRD4 degradation studies because of the known growth inhibition effects that result from BRD4 degradation.48 After treatment with PROTAC molecules Cpd 1, Cpd 2, Cpd 5, and Cpd 8, BRD4 was degraded in a dose-dependent manner, followed in potency by Cpd 9 and Cpd 3. Little or no BRD4 degradation was observed for Cpd 6 and Cpd 7 (Figure 4A). For MOA studies, we performed competition assays of Cpd 1 in the presence and absence of its precursor Cpd 10 (structure shown in Figure 3F), MG132 (a proteasome inhibitor), and 4-hydroxythalidomide. Western blot analysis (Figure 4B,C) demonstrates BRD4 rescue from degradation by these compounds, thereby demonstrating that Cpd 1, indeed, acted via an ubiquitin-proteasome system (UPS) mechanism. Given the structure similarity but different potencies of these compounds as BRD4 degraders in cells, these results suggest that different linker lengths and orientation of the POI and E3 ligase in the ternary complex induced by the PROTAC are important for ubiquitination and BRD4 degradation.

Figure 4.

Figure 4

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(A) Dose-dependent degradation of BRD4 in MV4;11 cells treated with the indicated concentrations of PROTACs for 24 h by Western blot analysis. (B) Degradation of BRD4 in MV4;11 cells after pretreatment with Cpd 1 precursor (Cpd 10), followed by Cpd 1 treatment for 24 h, to validate cellular BRD4 engagement. (C) BRD4 degradation in MV4;11 cells after pretreatment with 4-OH thalidomide or MG132, followed by Cpd 1 treatment for 24 h, to validate cellular CRBN engagement and proteasome dependency. (D,E) Kinetic comparisons of Cpd 1 and dBET1 for inducing degradation of BRD4 in MV4;11 cells. (F) Evaluation of BRD4 rebound in MDA-MB-468 cells by washout experiment. (G) Apoptosis induction comparison of Cpd 1, dBET1, and their precursors (Cpd 10, JQ1) in MV4;11 cells upon 24 h treatment with compounds (mean ± SD; n = 2; p-value calculated by two-tailed unpaired Student’s t test: * p < 0.05, ** p < 0.01, *** p < 0.001). (H) Antiproliferation assay in MV4;11 cells treated with increasing amounts of Cpd 1, dBET1, or their precursors (Cpd 10, JQ1) for 72 h (mean ± SD, n = 2).

We further compared the degradation properties of Cpd 1 and dBET1. When MV4;11 cells were treated with these PROTACs at 0.1 μM concentration, complete BRD4 degradation was observed in 0.5 h for Cpd 1 versus 2–3 h for dBET1 (Figure 4D). Moreover, for Cpd 1-treated cells, degradation of BRD4 persisted for at least 48 h. In contrast, BRD4 rebounded gradually starting from 8 h in cells treated by dBET1 (Figure 4E). We also performed a “washout” experiment where MV4;11 cells were treated with 0.1 μM Cpd 1 or dBET1 for 24 h, and then the compounds were removed by washing and replacement with fresh media. The BRD4 protein showed a slower and weaker rebound in Cpd 1-treated cells than dBET1-treated cells (Figure 4F). It should be noted that other BRD4 degraders, such as dBET6,49,50ARV825,51−53 and QCA-570(54,55) have been described that have superior potency, selectivity, and other pharmacological properties compared with dBET1. We also examined BRD4 degradation selectivity against the highly relevant BET family members, BRD2 and BRD3. Unfortunately, Cpd 1 did not have selective BRD4 degradation (data not shown).

Apoptosis and Antiproliferation

We performed apoptosis and antiproliferation assays for Cpd 1 and dBET1, along with their BRD4 binder precursors Cpd 10 and JQ1. Annexin V/PI (propidium iodide) double staining followed by flow cytometry analysis showed significant apoptosis induction by these PROTAC molecules. Cpd 1 is more effective than dBET1, while the precursors did not induce apoptotic cells (Figure 4G). In the antiproliferation assay, Cpd 1 showed stronger activity compared with dBET1 and is roughly 2 orders of magnitude more potent than Cpd 10 (Figure 4H). These results suggest that the inhibition of cell growth is attributed to BRD4 degradation, but not inhibition.

Conclusions

We have demonstrated the feasibility of utilizing DEL technology for library design, synthesis, and dual-protein affinity selection for direct BRD4 PROTAC discovery. This approach addresses the essential components of PROTAC discovery and optimization, cooperative binding of the PROTAC with the POI and E3 ligase, and the influence of the linker on this event, all of which are frequently considered most challenging because of multiple factors contributing to the degradation process. Importantly, the selection strategy can be applied to molecular glue discovery where positive cooperativity is a key requirement. Interestingly, similar work of BRD4/VHL PROTAC optimization using DEL approach has been recently reported with the DNA attachment point on the VHL ligand39 as an additional support of this strategy. Trivalent PROTACs targeting dual targets with a shared E3 ligase ligand have been reported and have shown potential pharmacological benefits.36−38 The combination of two strategies may allow the construction of a trivalent PROTAC library, and screening against both POIs and desired E3 ligases would be a very interesting direction for exploration.

With the increasing demands in the TPD field, including (1) strong competition in PROTAC discovery and development, (2) exploration of novel E3 ligases, and (3) AI-powered PROTAC discovery, there will be increasing demand for PROTAC molecule design, synthesis, screening, and validation. The DEL-based PROTAC synthesis and screening platform described here provides a cost-effective approach to meet this need. The direct discovery of PROTACs for difficult targets using our current PROTAC libraries and strategy may be challenging; however, we are confident that the utilization of larger DELs (1-trillion-member DELs, for example) to identify the POI binders, a target-specific PROTAC DEL synthesis on the basis of the identified POI binders, and screening will be advantageous over conventional approaches.

Methods

DEL Synthesis

The synthetic scheme of the PROTAC DEL is shown in Figure S2. First, acylation was applied in cycle 1 synthesis with 16 N-Boc and N-Fmoc dual-protected trifunctional acid–amine–amine linkers to attach DNA tags and yield 16 barcoded Conjugate 2. Then, 16 conjugates were pooled together, and Fmoc deprotection was performed, followed by a splitting into 522 portions for ligation with cycle 2 DNAs and acylation of 519 acid–aryl–halides and 3 nulls. Similarly, samples were pooled and split into 761 fractions for the ligation of cycle 3 DNAs and Suzuki coupling of 757 boronates plus 4 nulls, which yielded key library intermediates (Conjugate 7). Finally, N-Boc protection was removed, and half of the sample (Conjugate 8) was coupled with thalidomide-based carboxylate while the other half was left with primary amine. Both samples were ligated with different closing DNA barcodes to facilitate the PROTAC DEL and Control DEL synthesis, namely DEL1323–1 and DEL1323–3.

DEL Selection and DNA Sequencing

DEL selection was carried out using a KingFisher Duo Prime Purification System (ThermoFisher) in a 96-well plate. The incubation of 2.5 μM His-tagged CRBN/DDB1 (HitGen) and 2.5 μM GST-tagged BRD4 (Active Motif) with DEL took place in 100 μL of selection buffer (7.6 mM NaH2PO4, 12.4 mM Na2HPO4, 150 mM NaCl, 0.3 mg mL–1 ssDNA, 0.1% Tween-20, 10 mM imidazole, pH 7.0) for 1 h at RT. Then, equilibrated glutathione beads were added and incubated with DEL/protein sample in selection buffer at RT for 0.5 h to capture GST-BRD4, which was followed by a 1 min wash at RT in 500 μL of selection buffer for five times. The retained DEL members were recovered by heat elution in the elution buffer (18.7 mM NaH2PO4, 1.3 mM Na2HPO4, 300 mM NaCl, pH 5.5) at 85 °C for 15 min. Then, the elution was adjusted to pH 7.0 by the addition of NaOH. After the first step of selection, the second step was repeated with the heat-eluted portion of the previous step used as the input and incubated with fresh 2.5 μM His-tagged CRBN/DDB1 and 2.5 μM GST-tagged BRD4. Then His-tagged CRBN/DDB1 was captured by Ni beads, which was followed by washes and heat elution, as described above. After each step, the output was quantified by quantitative PCR. After the two steps of selection, the output was amplified by PCR, and sequencing was performed for PCR-amplified samples on an Illumina NovaSeq 6000 DNA sequencer. GST and DDB1 binders were excluded by setting corresponding controls during selection. The effect of binary binding was compared by setting Sample 3 with only GST-tagged BRD4 incubated with DEL for the first step and only His-tagged CRBN/DDB1 incubated with DEL for the second step.

Acknowledgments

We appreciate X.-M. Gong and Y. Zhang for their contribution to the project.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.2c00797.

  • Detailed PROTAC DEL design and synthesis, protein validation, DEL selection, off-DNA synthesis, and biological assays (PDF)

Author Contributions

∥ Q.C., C.L., and W.W. contributed equally.

The authors declare no competing financial interest.

Supplementary Material

cb2c00797_si_001.pdf (3.6MB, pdf)

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Data Citations

  1. Mason J.-W.; Hudson L.; Westphal M.-V.; Tutter A.; Michaud G.; Shu W.; Ma X.; Coley1 C.-W.; Clemons P.-A.; Bonazzi S.; Berst F.; Zécri F.-J.; Briner K.; Schreiber S.-L.. DNA-encoded library (DEL)-enabled discovery of proximity-inducing small molecules. bioRxiv, October, 17, 2022, 512184. 10.1101/2022.10.13.512184. [DOI] [PMC free article] [PubMed]

Supplementary Materials

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