Drug Modalities Research Articles

DELs enable the development of BRET probes for target engagement studies in cells

DNA-encoded libraries (DELs) provide unmatched chemical diversity and starting points for novel drug modalities. Here, we describe a workflow that exploits the bifunctional attributes of DEL ligands as a platform to generate BRET probes for live cell target engagement studies. To establish proof of concept, we performed a DEL screen using aurora kinase A and successfully converted aurora DEL ligands as cell-active BRET probes. Aurora BRET probes enabled the validation and stratification of the chemical series identified from primary selection data. Furthermore, we have evaluated the effective repurposing of pre-existing DEL screen data to find suitable leads for BRET probe development. Our findings support the use of DEL workflows as an engine to create cell-active BRET probes independent of structure or compound SAR. The combination of DEL and BRET technology accelerates hit-to-lead studies in a live cell setting.

Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group.

Excipients are essential components within drug products that contribute significantly to their overall quality, effectiveness, and safety. There is a lack of global, harmonized guidance relating to the non-clinical testing of novel excipients which is perceived to create uncertainty and strategic risk, potentially hindering innovation and disincentivizing their use. To test these perceptions, the IQ Novel Excipient Working Group surveyed member companies regarding their main concerns and prior experience regarding the non-clinical evaluation of excipients. Of the 19 respondents, 13 provided, collectively, 33 non-clinical program examples supporting the development of novel excipients. Programs were distributed across a range of therapeutic areas and included a variety of drug modalities and administration routes. Package designs were variable, but where possible, employed the use of existing data, supplemented with new toxicology studies as appropriate. Of the programs which had submitted data to regional health authorities, only three received feedback requesting additional studies or that demonstrated differences in regional opinion. In addition, companies provided recommendations on how the current (or new) guidance related to non-clinical excipient evaluation (and other areas, such as Chemistry, Manufacturing, and Controls and databases) may be improved.

An enzyme cascade enables production of therapeutic oligonucleotides in a single operation.

Therapeutic oligonucleotides have emerged as a powerful drug modality with the potential to treat a wide range of diseases; however, the rising number of therapies poses a manufacturing challenge. Existing synthetic methods use stepwise extension of sequences immobilized on solid supports and are limited by their scalability and sustainability. We report a biocatalytic approach to efficiently produce oligonucleotides in a single operation where polymerases and endonucleases work in synergy to amplify complementary sequences embedded within catalytic self-priming templates. This approach uses unprotected building blocks and aqueous conditions. We demonstrate the versatility of this methodology through the synthesis of clinically relevant oligonucleotide sequences containing diverse modifications.

Machine learning optimization of candidate antibody yields highly diverse sub-nanomolar affinity antibody libraries

Therapeutic antibodies are an important and rapidly growing drug modality. However, the design and discovery of early-stage antibody therapeutics remain a time and cost-intensive endeavor. Here we present an end-to-end Bayesian, language model-based method for designing large and diverse libraries of high-affinity single-chain variable fragments (scFvs) that are then empirically measured. In a head-to-head comparison with a directed evolution approach, we show that the best scFv generated from our method represents a 28.7-fold improvement in binding over the best scFv from the directed evolution. Additionally, 99% of designed scFvs in our most successful library are improvements over the initial candidate scFv. By comparing a library’s predicted success to actual measurements, we demonstrate our method’s ability to explore tradeoffs between library success and diversity. Results of our work highlight the significant impact machine learning models can have on scFv development. We expect our method to be broadly applicable and provide value to other protein engineering tasks.

Steroids in Headache: A Comprehensive Review of Recent Research.

Headache is an extremely common symptom of the general outpatient department and also the headache clinic, with prevalence of 48.9% in the general population. None has ever experienced headache in life time. Headache is seen in 1 patient out of 10 general practitioner (GP) consultations, 1 referral out of 3 is headache in neurology OPD, and 1 in 5 of all emergency medical admissions. Of all headaches, around 98% constitute primary headache: migraine without aura, tension headache, and cluster headache. With advancement in various drug modalities, certain headache forms respond less well to the regular approved medications, and some headaches are complicated by the analgesic itself. Steroids have been tried in many subtypes of headache, especially in primary forms of headache with dysautonomia, headache with trigeminal pathway activation and disinhibition, and in certain medication-culprit headaches. This subgroup of headaches is almost a challenge in an emergency for the headache expert as well. So, we need to assess the role of steroids in less well-responsive headaches. Current reviewed evidence on the role of steroids in primary headache suggests that steroids have a role in status migrainosus and medication overuse headache when used in the mentioned and monitored manner. Consideration and further exploration of its role in other primary headaches may reveal insight into steroid efficacy as a treatment modality in various subtypes of headache. Steroids, when used cautiously in specifically selected primary headaches under supervision, proved miraculous where other modalities failed.

Preclinical evaluation of novel HER3-targeting radioconjugates for the imaging and treatment of HER3-expressing cancers.

e15114 Background: HER3 overexpression in tumors is associated with poor survival and is implicated in drug resistance mechanisms of HER1 (EGFR) and HER2 targeted therapies. Although antibodies against HER3 have been developed and evaluated in clinical trials, no HER3 targeted therapy has been approved, underscoring the unmet need for novel HER3 therapeutic approaches. We hypothesized that HER3 radioligand targeted therapies could provide enhanced therapeutic efficacy against HER3-positive cancers through the energy deposited by alpha or beta emitting radionuclides in tumor cells. Here we describe the development and preclinical evaluation of novel anti-HER3 antibody radioconjugates (ARCs), 225Ac-HER3 and 177Lu-HER3, using the alpha-emitting Actinium-225 (225Ac) and beta-emitting Lutetium-177 (177Lu) radioisotopes, respectively. Methods: ARCs were prepared by radiolabeling HER3 antibody with 225Ac or 177Lu using S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) to yield 225Ac or 177Lu-HER3-ARCs. DOTA modified antibodies were characterized by HPLC and MALDI-TOF and HER3-ARCs were fully characterized by instant thin-layer chromatography (iTLC) and HPLC. The in vitro binding properties of the HER3-ARCs were evaluated using HER3 recombinant proteins and cells expressing HER3 in ELISA and flow cytometry. The in vivo pharmacological properties of the HER3-ARCs were evaluated by molecular imaging using Zirconium-89 (89Zr) Positron Emission Tomography (PET), biodistribution and antitumor efficacy studies. Results: HER3 antibody was successfully modified with p-SCN-Bn-DOTA to yield a conjugate with approximately 8 DOTAs per antibody molecule. Results from the in vitro binding assays of ARCs to either HER3 human recombinant protein or cells expressing HER3 demonstrated similar binding properties of 225Ac-HER3 and 177Lu-HER3 to unmodified HER3 antibody. The biodistribution study in NCI-H1975 tumor bearing mice showed that both 225Ac-HER3 and 177Lu-HER3-ARCs specifically accumulate in HER3-expressing tumors relative to other tissues. In agreement with the biodistribution studies, PET images revealed specific uptake of 89Zr-HER3 in NCI-H1975 tumors. Furthermore, 225Ac and 177Lu-HER3-ARCs showed significantly more potent NCI-H1975 tumor growth inhibition compared to controls. Conclusions: Our findings suggest that a HER3 targeted radiotherapy approach can enhance therapeutic response and overcome the limitations of previously explored HER3 targeted drug modalities. Thus, further preclinical evaluation of 225Ac-HER3 and 177Lu-HER3 is warranted, including in settings of tumor drug resistance, which can provide the basis for investigating HER3-ARCs as an effective treatment approach in future clinical trials.

Phase I safety and preliminary efficacy of PM1003, a bispecific antibody targeting PD-L1 and 4-1BB, in patients with advanced solid tumors.

e14511 Background: PM1003 is a VHH-based anti-PD-L1/4-1BB bispecific antibody. The anti-4-1BB VHH arm binds to a unique epitope at the CRD4 region of 4-1BB, activating 4-1BB signals through cross-linking in the presence of PD-L1 that is often upregulated in the tumor microenvironment, thus avoiding harm to healthy tissues. This is the First In Human study of PM1003. Methods: This study was conducted with a standard 3+3 dose escalation design (Part A: single doses of 0.02, 0.1, 1, 3, 6, and 10 mg/kg for DLT evaluation after 3 weeks followed by Q2W for further administration) and dose expansion (Part B). For Part A, the primary endpoint was safety and tolerability with secondary endpoint of ORR per RECIST 1.1. For Part B, ORR per RECIST 1.1 was the primary endpoint and the secondary endpoints were safety and PK. Results: As of February 9, 2023, a total of 17 subjects have received at least 1 dose of PM1003, including 16 subjects in Part A (3 subjects in each of the 0.02, 0.1, 1, 3 mg/kg dose levels respectively and 4 subjects in 6 mg/kg), and 1 subject in Part B (1 mg/kg Q2W). In Part A, no DLTs were observed up to 6 mg/kg. Of the 17 patients, TRAEs occurred in 15 subjects (88.2%), ≥ Grade 3 TRAEs occurred in 5 subjects (29.4%). No patient discontinued PM1003 administration due to TRAE. The most common TRAEs were anaemia (35.3%), neutrophil count decreased (29.4%), white blood cell count decreased (29.4%), platelet count decreased (29.4%), fatigue (23.5%). 11 subjects completed at least one efficacy evaluation in part A. The median duration of PM1003 exposure was 9.9 weeks (range, 3.1-31.1 weeks). The ORR per RECIST 1.1 was 9.1% with a DCR of 54.5%. Preliminary evidence of antitumor activity has been observed in 1 subject with gastric cancer (1 mg/kg Q2W) who was enrolled after previous surgery, chemotherapy, anti-PD-1 and anti-HER2-ADC treatment, and had a partial response of 87.8% in target lesion reduction during the first efficacy evaluation (7 weeks) after PM1003 treatment. T1/2 of PM1003 of 1 mg/kg and 3 mg/kg dose level is 6.3 and 12.8 days, respectively. Receptor occupancy of PD-L1 in the 1 mg/kg and 3 mg/kg cohorts reached saturation at 336 hours after the first single dose and maintained at an almost stable state. Conclusions: PM1003 was well-tolerated up to 6 mg/kg and has shown preliminary anti-tumor activity in a patient who was previously treated with multiple drug modalities including anti-PD-1. The dose-escalation at 10 mg/kg and dose expansion are ongoing. Clinical trial information: ChiCTR2100052887 .

Industry perspective on the nonclinical safety assessment of heterobifunctional degraders

Targeted protein degraders (TPDs), which act through the ubiquitin proteasome system (UPS), are one of the newest small-molecule drug modalities. Since the initiation of the first clinical trial in 2019, investigating the use of ARV-110 in patients with cancer, the field has rapidly expanded. Recently, some theoretical absorption, distribution, metabolism, and excretion (ADME) and safety challenges have been posed for the modality. Using these theoretical concerns as a framework, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) Protein Degrader Working Group (WG) conducted two surveys to benchmark current preclinical practices for TPDs. Conceptually, the safety assessment of TPDs is the same as for standard small molecules; however, the techniques used, assay conditions/study endpoints, and timing of assessments might need to be modified to address differences in mode of action of the class.

Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers

Nucleic acid therapeutics are becoming an important drug modality, offering the unique opportunity to address "undruggable" targets, respond rapidly to evolving pathogens, and treat diseases at the gene level for precision medicine. However, nucleic acid therapeutics have poor bioavailability and are chemolabile and enzymolabile, imposing the need for delivery vectors. Dendrimers, by virtue of their well-defined structure and cooperative multivalence, represent precision delivery systems. We synthesized and studied bola-amphiphilic dendrimers for cargo-selective and on-demand delivery of DNA and small interfering RNA (siRNA), both important nucleic acid therapeutics. Remarkably, superior performances were achieved for siRNA delivery with the second-generation dendrimer, yet for DNA delivery with the third generation. We systematically studied these dendrimers with regard to cargo binding, cellular uptake, endosomal release, and invivo delivery. Differences in size both of the dendrimers and their nucleic acid cargos impacted the cooperative multivalent interactions for cargo binding and release, leading to cargo-adaptive and selective delivery. Moreover, both dendrimers harnessed the advantages of lipid and polymer vectors, while offering nanotechnology-based tumor targeting and redox-responsive cargo release. Notably, they allowed tumor- and cancer cell-specific delivery of siRNA and DNA therapeutics for effective treatment in different cancer models, including aggressive and metastatic malignancies, outperforming the currently available vectors. This study provides avenues to engineer tailor-made vectors for nucleic acid delivery and precision medicine.

Enzymatic Bioconjugation: A Perspective from the Pharmaceutical Industry.

Enzymes have firmly established themselves as bespoke catalysts for small molecule transformations in the pharmaceutical industry, from early research and development stages to large-scale production. In principle, their exquisite selectivity and rate acceleration can also be leveraged for modifying macromolecules to form bioconjugates. However, available catalysts face stiff competition from other bioorthogonal chemistries. In this Perspective, we seek to illuminate applications of enzymatic bioconjugation in the face of an expanding palette of new drug modalities. With these applications, we wish to highlight some examples of current successes and pitfalls of using enzymes for bioconjugation along the pipeline and try to illustrate opportunities for further development.

Strengthening the Competitiveness of Japan's Pharmaceutical Industry: Analysis of Country Differences in the Origin of New Drugs and Japan's Highly Productive Firm.

Improving the new drug discovery and development capability of the Japanese pharmaceutical industry, which shows a huge trade deficit, is an urgent issue. To tackle this issue and propose remedies, this study analyzed the originators and characteristics of new drugs approved by the Food and Drug Administration (FDA) from 2017 to 2022 and examined the contributions of Japanese companies. Analysis of the establishment year of the companies that created the approved drugs showed that bio-ventures established in the 1990s and 2000s highly contributed to the creation of the approved drugs in regions other than Japan (particularly in the US), whereas, in Japan, all approved drugs were created by old incumbent pharmaceutical companies. This suggests the presence of an urgent need in Japan to foster start-ups that link scientific discoveries and technologies in academia to drug discovery. The novelty of approved drugs measured by the ratio of first-in-class, orphan drug, and recent drug modalities did not differ between Japan and other countries, suggesting that Japanese pharmaceutical companies follow the technological trends of new drugs. A case analysis of Kyowa Kirin, the Japanese company that created the largest number of the drugs approved by the FDA from 2017 to 2022 among Japanese companies, suggests that focused investment in modality technology development, strengthening collaboration with academia in biology, and the reutilization of small-molecule drug discovery capabilities are important for improving drug discovery productivity.

Development and Evaluation of Brain-targeted Drug and Gene Delivery System

New drug modalities such as nucleic acid, gene, cells, and nanoparticles are expected for treating refractory diseases. However, these drugs have larger size and low cell membrane permeability; therefore, drug delivery systems (DDS) are essential for delivery to the intended site at the organ and cellular level. In case of the brain, drug migration to the brain from blood circulation is extremely limited by the blood-brain barrier (BBB). Therefore, brain-targeted DDS technologies with the ability to overcome the BBB are being intensively developed. Ultrasound-mediated BBB opening can transiently permeabilize the BBB via cavitation and oscillation and is expected to transfer drugs into the brain. Besides several fundamental studies, clinical studies on BBB opening have also been undertaken, proving its efficacy and safety. Our group has developed an ultrasound-mediated DDS to the brain for low-molecular weight drugs as well as plasmid DNA and mRNA intended for gene therapy. We also evaluated the distribution of gene expression to obtain essential information for applying gene therapy. Here, I provide general information on DDS to the brain, and describe our research progress in brain-targeted delivery of plasmid DNA and mRNA using BBB opening.

Modality-DTA: Multimodality Fusion Strategy for Drug-Target Affinity Prediction.

Prediction of the drug-target affinity (DTA) plays an important role in drug discovery. Existing deep learning methods for DTA prediction typically leverage a single modality, namely simplified molecular input line entry specification (SMILES) or amino acid sequence to learn representations. SMILES or amino acid sequences can be encoded into different modalities. Multimodality data provide different kinds of information, with complementary roles for DTA prediction. We propose Modality-DTA, a novel deep learning method for DTA prediction that leverages the multimodality of drugs and targets. A group of backward propagation neural networks is applied to ensure the completeness of the reconstruction process from the latent feature representation to original multimodality data. The tag between the drug and target is used to reduce the noise information in the latent representation from multimodality data. Experiments on three benchmark datasets show that our Modality-DTA outperforms existing methods in all metrics. Modality-DTA reduces the mean square error by 15.7% and improves the area under the precisionrecall curve by 12.74% in the Davis dataset. We further find that the drug modality Morgan fingerprint and the target modality generated by one-hot-encoding play the most significant roles. To the best of our knowledge, Modality-DTA is the first method to explore multimodality for DTA prediction.

The Potential Impact of New Drug and Therapeutic Modalities on Drug Resistance to Renal Cell Carcinoma.

The treatment of advanced renal cell carcinoma has been substantially improved by the introduction of targeted and immune therapies and their respective combinations. Unleashing the activity of the immune system opened a new and successful front in the fight against cancers. Despite the benefits, drug resistance phenomena and adverse side effects can compromise efficacy. The development of new modalities of drugs and therapies with properties and mechanisms of action that break away from conventional medicines was expanded in recent years. This perspective discusses the prospects of these innovative and highly potent novel treatments in overcoming much of the current issues surrounding the resistance to approved renal cell carcinoma treatments and the challenges facing their introduction.

BioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements.

Monoclonal antibody therapies targeting immuno-modulatory targets such as checkpoint proteins, chemokines, and cytokines have made significant impact in several areas, including cancer, inflammatory disease, and infection. However, antibodies are complex biologics with well-known limitations, including high cost for development and production, immunogenicity, a limited shelf-life because of aggregation, denaturation, and fragmentation of the large protein. Drug modalities such as peptides and nucleic acid aptamers showing high-affinity and highly selective interaction with the target protein have been proposed alternatives to therapeutic antibodies. The fundamental limitation of short in vivo half-life has prevented the wide acceptance of these alternatives. Covalent drugs, also known as targeted covalent inhibitors (TCIs), form permanent bonds to target proteins and, in theory, eternally exert the drug action, circumventing the pharmacokinetic limitation of other antibody alternatives. The TCI drug platform, too, has been slow in gaining acceptance because of its potential prolonged side-effect from off-target covalent binding. To avoid the potential risks of irreversible adverse drug effects from off-target conjugation, the TCI modality is broadening from the conventional small molecules to larger biomolecules possessing desirable properties (e.g., hydrolysis resistance, drug-action reversal, unique pharmacokinetics, stringent target specificity, and inhibition of protein-protein interactions). Here, we review the historical development of the TCI made of bio-oligomers/polymers (i.e., peptide-, protein-, or nucleic-acid-type) obtained by rational design and combinatorial screening. The structural optimization of the reactive warheads and incorporation into the targeted biomolecules enabling a highly selective covalent interaction between the TCI and the target protein is discussed. Through this review, we hope to highlight the middle to macro-molecular TCI platform as a realistic replacement for the antibody.

Rapid synthesis of bismuth-organic frameworks as selective antimicrobial materials against microbial biofilms.

Antibiotic resistance is a global public health threat, and urgent actions should be undertaken for developing alternative antimicrobial strategies and approaches. Notably, bismuth drugs exhibit potent antimicrobial effects on various pathogens and promising efficacy in tackling SARS-CoV-2 and related infections. As such, bismuth-based materials could precisely combat pathogenic bacteria and effectively treat the resultant infections and inflammatory diseases through a controlled release of Bi ions for targeted drug delivery. Currently, it is a great challenge to rapidly and massively manufacture bismuth-based particles, and yet there are no reports on effectively constructing such porous antimicrobial-loaded particles. Herein, we have developed two rapid approaches (i.e., ultrasound-assisted and agitation-free methods) to synthesizing bismuth-based materials with ellipsoid- (Ellipsoids) and rod-like (Rods) morphologies respectively, and fully characterized physicochemical properties. Rods with a porous structure were confirmed as bismuth metal-organic frameworks (Bi-MOF) and aligned with the crystalline structure of CAU-17. Importantly, the formation of Rods was a 'two-step' crystallization process of growing almond-flake-like units followed by stacking into the rod-like structure. The size of Bi-MOF was precisely controlled from micro-to nano-scales by varying concentrations of metal ions and their ratio to the ligand. Moreover, both Ellipsoids and Rods showed excellent biocompatibility with human gingival fibroblasts and potent antimicrobial effects on the Gram-negative oral pathogens including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Fusobacterium nucleatum. Both Ellipsoids and Rods at 50​μg/mL could disrupt the bacterial membranes, and particularly eliminate P.gingivalis biofilms. This study demonstrates highly efficient and facile approaches to synthesizing bismuth-based particles. Our work could enrich the administration modalities of metallic drugs for promising antibiotic-free healthcare.

Passive Membrane Permeability of Sizable Acyclic β-Hairpin Peptides.

The recent shift toward increasingly larger drug modalities has created a significant demand for novel classes of compounds with high membrane permeability that can inhibit intracellular protein-protein interactions (PPIs). While major advances have been made in the design of cell-permeable helices, stapled β-sheets, and cyclic peptides, the development of large acyclic β-hairpins lags far behind. Therefore, we investigated a series of 26 β-hairpins (MW > 1.6 kDa) belonging to a chemical space far beyond the Lipinski "rule of five" (fbRo5) and showed that, in addition to their innate plasticity, the lipophilicity of these peptides (logD 7.4 ≈ 0 ± 0.7) can be tuned to drastically improve the balance between aqueous solubility and passive membrane permeability.

Small Extracellular Vesicles as a New Class of Medicines.

Extracellular vesicles (EVs) are nanovesicles that are naturally released from cells in a lipid bilayer-bound form. A subset population with a size of 200 nm, small EVs (sEVs), is enticing in many ways. Initially perceived as mere waste receptacles, sEVs have revealed other biological functions, such as cell-to-cell signal transduction and communication. Besides their notable biological functions, sEVs have profound advantages as future drug modalities: (i) excellent biocompatibility, (ii) high stability, and (iii) the potential to carry undruggable macromolecules as cargo. Indeed, many biopharmaceutical companies are utilizing sEVs, not only as diagnostic biomarkers but as therapeutic drugs. However, as all inchoate fields are challenging, there are limitations and hindrances in the clinical translation of sEV therapeutics. In this review, we summarize different types of sEV therapeutics, future improvements, and current strategies in large-scale production.

Computationally profiling peptide:MHC recognition by T-cell receptors and T-cell receptor-mimetic antibodies.

T-cell receptor-mimetic antibodies (TCRms) targeting disease-associated peptides presented by Major Histocompatibility Complexes (pMHCs) are set to become a major new drug modality. However, we lack a general understanding of how TCRms engage pMHC targets, which is crucial for predicting their specificity and safety. Several new structures of TCRm:pMHC complexes have become available in the past year, providing sufficient initial data for a holistic analysis of TCRms as a class of pMHC binding agents. Here, we profile the complete set of TCRm:pMHC complexes against representative TCR:pMHC complexes to quantify the TCR-likeness of their pMHC engagement. We find that intrinsic molecular differences between antibodies and TCRs lead to fundamentally different roles for their heavy/light chains and Complementarity-Determining Region loops during antigen recognition. The idiotypic properties of antibodies may increase the likelihood of TCRms engaging pMHCs with less peptide selectivity than TCRs. However, the pMHC recognition features of some TCRms, including the two TCRms currently in clinical trials, can be remarkably TCR-like. The insights gained from this study will aid in the rational design and optimisation of next-generation TCRms.

Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods.

Proteolysis targeting chimera (PROTAC) is a novel drug modality that facilitates the degradation of a target protein by inducing proximity with an E3 ligase. In this work, we present a new computational framework to model the cooperativity between PROTAC-E3 binding and PROTAC-target binding principally through protein-protein interactions (PPIs) induced by the PROTAC. Due to the scarcity and low resolution of experimental measurements, the physical and chemical drivers of these non-native PPIs remain to be elucidated. We develop a coarse-grained (CG) approach to model interactions in the target-PROTAC-E3 complexes, which enables converged thermodynamic estimations using alchemical free energy calculation methods despite an unconventional scale of perturbations. With minimal parametrization, we successfully capture fundamental principles of cooperativity, including the optimality of intermediate PROTAC linker lengths that originates from configurational entropy. We qualitatively characterize the dependency of cooperativity on PROTAC linker lengths and protein charges and shapes. Minimal inclusion of sequence- and conformation-specific features in our current force field, however, limits quantitative modeling to reproduce experimental measurements, but further development of the CG model may allow for efficient computational screening to optimize PROTAC cooperativity.