Protein Degraders Redefine ADME And Drug Disposition Dynamics

By Nicole Alizade

The ADME principles — absorption, distribution, metabolism, and excretion — have been a cornerstone of medicinal chemistry for many decades. Factors such as high exposure, linear pharmacokinetics, and predictable clearance were inevitably taken into consideration for newly developed therapies to be successful. These requirements urged the current landscape to prioritize the development of lipophilic, compact, and stable small molecules.

However, this orthodoxy has been recently challenged by the emergence of protein degraders, or proteolysis-targeting chimeras (PROTACs) — a category of heterobifunctional molecules that selectively trigger the destruction of intracellular targets. These degraders catalyze complete elimination, as opposed to inhibitors, which block target protein activity through sustained occupancy of the active site. This biological process is done by initiation of a catalytic cycle of destruction through the recruitment of the ubiquitin-proteasome system (UPS) to tag unneeded proteins.^1,2 The advancements in this domain fundamentally alter how we view pharmacokinetics (PK), pharmacodynamics (PD), and the ADME framework — all due to the fact that these molecules behave catalytically instead of stoichiometrically.

The Structural Paradox

Traditional drug discovery pipelines follow Lipinski's rule of five. Protein degraders, however, break the dependency on those rules without breaking functionality. Currently, most PROTACs weigh between 700 and 1,200 Da and exhibit high polarity, multiple rotatable bonds, and low lipophilicity. All these traits are associated with poor bioavailability and permeability, but many of these molecules are active within in vivo systems.⁴ This paradox brings a shift in which properties matter for efficiency — the catalytic nature of these degraders signifies that drug potency is less dependent on plasma concentration and more on intracellular access and persistence.⁵

Absorption: The Folding Frontier

As mentioned above, despite poor solubility and elevated polarity of degraders, many possess effective absorption capabilities, defying traditional logic. One reason for this, supported by emerging evidence, is conformational dynamics — certain PROTACs can transiently adopt compact, lipophilic shapes that can passively permeate membranes.⁶ This phenomenon is called “induced fit permeability.”⁷ Another major underlying reason is the employment of transporter-mediated uptake. For instance, some PROTACs are substrates for efflux transporters, such as P-glycoprotein, influencing their intracellular accumulation and pharmacokinetic profile.⁸

These mechanisms show that permeability is not only due to the lipophilicity of molecules, but also to conformation and their transport. Meanwhile, several formulation innovations, such as nanoencapsulation, prodrug masking, and linker rigidification, are being pursued to improve oral bioavailability.^9,10 Such translation will likely depend on integrating formulation engineering early in lead optimization rather than as a late-stage rescue. Yet the key lesson from first-generation PROTACs remains the fact that systemic exposure does not equal efficacy.

Distribution: Location Is Everything

In traditional PK, distribution is examined at the tissue or plasma level. This contrasts with degraders, where it is done at the subcellular scale. This activity depends on spatial co-localization of the degrader, its target, and the recruited E3 ligase.⁸ The tissue distributions of versatile E3 ligases — such as VHL, CRBN, or MDM2 — vary widely, meaning the same degrader can be active in one cell and inefficient in another.¹¹ This cellular geography introduces an additional layer of complexity. Traditional exposure metrics, such as maximal concentration (C_max) and AUC, fail to predict efficacy as the drug elimination does not equal target recovery. Instead, new parameters, such as effective concentration (C_eff) and degradation rate constants (k_deg), may provide better correlation between two parameters.¹² Additionally, as per event-driven pharmacology, effects initiated by the degraders persist even after plasma levels drop. Studies using fluorescence resonance energy transfer (FRET) and high-affinity binary technology (HiBiT) degradation sensors can prove this hypothesis through the visualization of degradation kinetics in real time, which reveals heterogeneous knockdown patterns within different cell populations.¹³

Metabolism: Hit-And-Run Pharmacology

A molecule’s fate is defined by metabolism — but for degraders, its objective is often terminated before being processed. Degraders’ catalytic nature elucidates that a transient presence can result in lasting biological effects. A short pulse of a PROTAC can eliminate its target for a duration of several hours to days, disconnecting traditional metabolic clearance and pharmacological duration.² This requires the development of new PK/PD models that include target resynthesis and cellular recovery in addition to the plasma half-life.

As large, flexible linkers tend to be prone to oxidative degradation and/or hydrolysis, metabolic liability remains an issue.¹⁴ Medicinal chemists are opting to employ metabolite-guided optimizations, such as engineering conformationally restricted linkers, shielding hydrogen bond donors, and designing macrocyclic scaffolds to resist metabolic oxidation and improve oral bioavailability.¹⁵ A final challenge in this domain that remains is metabolite functionality. If fragments affine partially in binding to either to E3 ligase or the target protein, they could act as competitive inhibitors and alter degradation efficiency. Therefore, metabolite profiling should evolve toward an analysis of functional outcomes, beyond simply monitoring parent elements.

Excretion: Persistence Of The Effects

The end of a molecule’s life cycle is marked by excretion, but this does not necessarily mark the end of its effect. Once the target protein is degraded, its recovery depends entirely on protein synthesis and not on the drug's presence. This decoupling mechanism is responsible for a temporal lag between chemical disappearance and biological restoration, known as the pharmacological memory. This persistence allows intermittent dosing while complicating safety evaluation for essential proteins and tissues with slow turnover. Taking this into account, physiologically based pharmacokinetic (PBPK) models are integrating protein turnover kinetics with metabolic excretion parameters to predict the duration of the effect more accurately.^16,17

ADME Screening: The Next-Generation Toolkit

Traditional ADME screens — such as Caco-2 permeability assays, microsomal stability, and cytochrome P450 (CYP) inhibition — capture little of what influences the degrader’s efficiency.^18,19 Therefore, the field is actively transitioning toward mechanistic, live-cell, and proteome-scale assays. Some of the emerging technologies include:

• nanoBRET/HiBiT degradation assays for kinetic readouts²⁰
• E3 ligase expression mapping for tissue-selective modeling²¹
• fluorescent degrader uptake imaging for permeability profiling²²
• target resynthesis recovery assays for durability measurement²³

Data derived from these sources then get integrated into multiparameter AI models that can accurately predict degradation efficiency from the given chemical structure, ternary complex stability, and target turnover simultaneously.²⁴ These pipelines show that ADME is evolving from simple static assays to dynamic system models. This fusion of chemical biology, proteomics, and machine learning represents the beginning of a new era of computational degradomics — a field whose main objective is quantifying degradation as both a chemical and biological process.

From ADME To ABDE: A Conceptual Reframing

PROTACs reveal the limits of traditional pharmacology. The classic PK/PD relationship is inverted through these degraders’ event-driven mode of action. Their efficacy no longer scales with exposure but instead with the probability of the event of productive ternary complex formation between the degrader, target protein, and the ligase. Consequently, the concepts of drug bioavailability and clearance lose their predictive value in the domain of PROTACs. Instead, we can introduce the term of ABDE, which stands for:

Absorption: how the molecule accesses the intracellular environment

Biodistribution: areas where the aforementioned ternary complexes can form

Degradation: how effectively the target is destroyed

Elimination: how long before the system resets to its original value

Therefore, ABDE replaces ADME, which becomes an analytical framework for induced proximity therapeutics rather than common inhibitors.

The Role Of AI And Systems Pharmacology

The gap between chemistry and systems biology is being closed by the emergence of machine learning. AI models can now simulate the effects of degrader structures on ternary complex stability, membrane permeability, and degradation kinetics. Meanwhile, proteome-wide spectrometry approaches, such as multiplexed tandem mass tag (TMT)-based or data-independent acquisition (DIA) workflows, provide the ability to identify extensive on- and off-target degradation events in real biological contexts. Together, these tools are enabling the emergence of digital twin simulations, predicting the unique behavioral pattern of a specific PROTAC across tissues and time. The future of ADME science will therefore be more heavily based on integrative modeling, combining chemical properties with in vivo context, proteomic dynamics, and transcriptional feedback loops.^25,26,27

Toward A Post-Lipinski Era

In conclusion, novel protein degraders mark a turning point in how we conceptualize medicines due to their catalytic, self-limiting, and spatially defined action. This challenges every assumption accepted in the traditional ADME theory. We’re made to rethink the biological essence of pharmacology by trying to answer the question of what is made by PROTACs once they arrive at their target location.

Following this trend, the next generation of drug discovery will be about engineering biological events with precision, persistence, and predictability instead of focusing exclusively on extending half-lives or optimizing properties. As the movement beyond the Lipinski paradigm becomes irrefutable, one truth remains clear: ADME isn’t becoming irrelevant, but it is evolving into a language that can speak the dialect of biology.

References:

1. K. M. Sakamoto, K. B. Kim, A. Kumagai, F. Mercurio, C. M. Crews, and R. J. Deshaies, “Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation,” Proc. Natl. Acad. Sci. U.S.A., vol. 98, no. 15, pp. 8554–8559, Jul. 2001, doi: 10.1073/pnas.141230798.
2. D. P. Bondeson et al., “Catalytic in vivo protein knockdown by small molecule PROTACs,” Nat Chem Biol, vol. 11, no. 8, pp. 611–617, Aug. 2015, doi: 10.1038/nchembio.1858.
3. V. Poongavanam, B. C. Doak, and J. Kihlberg, “Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space,” Current Opinion in Chemical Biology, vol. 44, pp. 23–29, Jun. 2018, doi: 10.1016/j.cbpa.2018.05.010.
4. M. Békés, D. R. Langley, and C. M. Crews, “PROTAC targeted protein degraders: the past is prologue,” Nat Rev Drug Discov, vol. 21, no. 3, pp. 181–200, Mar. 2022, doi: 10.1038/s41573-021-00371-6.
5. I. Churcher, “Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?,” J. Med. Chem., vol. 61, no. 2, pp. 444–452, Jan. 2018, doi: 10.1021/acs.jmedchem.7b01272.
6. V. Poongavanam et al., “Linker-Dependent Folding Rationalizes PROTAC Cell Permeability,” J. Med. Chem., vol. 65, no. 19, pp. 13029–13040, Oct. 2022, doi: 10.1021/acs.jmedchem.2c00877.
7. Y. Atilaw et al., “Solution Conformations Shed Light on PROTAC Cell Permeability,” ACS Med. Chem. Lett., vol. 12, no. 1, pp. 107–114, Jan. 2021, doi: 10.1021/acsmedchemlett.0c00556.
8. M. S. Gadd et al., “Structural basis of PROTAC cooperative recognition for selective protein degradation,” Nat Chem Biol, vol. 13, no. 5, pp. 514–521, May 2017, doi: 10.1038/nchembio.2329.
9. N. L. Tran, G. A. Leconte, and F. M. Ferguson, “Targeted Protein Degradation: Design Considerations for PROTAC Development,” Curr Protoc, vol. 2, no. 12, p. e611, Dec. 2022, doi: 10.1002/cpz1.611.
10. A. Testa, S. J. Hughes, X. Lucas, J. E. Wright, and A. Ciulli, “Structure-Based Design of a Macrocyclic PROTAC,” Angew Chem Int Ed Engl, vol. 59, no. 4, pp. 1727–1734, Jan. 2020, doi: 10.1002/anie.201914396.
11. C. Mayor-Ruiz and G. E. Winter, “Identification and characterization of cancer vulnerabilities via targeted protein degradation,” Drug Discovery Today: Technologies, vol. 31, pp. 81–90, Apr. 2019, doi: 10.1016/j.ddtec.2018.12.003.
12. H. Zhao and F. Narjes, “Kinetic Modeling of PROTAC‐Induced Protein Degradation,” ChemMedChem, vol. 18, no. 24, p. e202300530, Dec. 2023, doi: 10.1002/cmdc.202300530.
13. K. M. Riching et al., “Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action,” ACS Chem Biol, vol. 13, no. 9, pp. 2758–2770, Sep. 2018, doi: 10.1021/acschembio.8b00692.
14. R. I. Troup, C. Fallan, and M. G. J. Baud, “Current strategies for the design of PROTAC linkers: a critical review,” Explor Target Antitumor Ther, vol. 1, no. 5, pp. 273–312, 2020, doi: 10.37349/etat.2020.00018.
15. G. Zhong, X. Chang, W. Xie, and X. Zhou, “Targeted protein degradation: advances in drug discovery and clinical practice,” Sig Transduct Target Ther, vol. 9, no. 1, pp. 1–45, Nov. 2024, doi: 10.1038/s41392-024-02004-x.
16. S. Guzzetti and P. Morentin Gutierrez, “An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions,” J Pharmacokinet Pharmacodyn, vol. 50, no. 5, pp. 327–349, Oct. 2023, doi: 10.1007/s10928-023-09857-9.
17. X. Zhuang and C. Lu, “PBPK modeling and simulation in drug research and development,” Acta Pharm Sin B, vol. 6, no. 5, pp. 430–440, Sep. 2016, doi: 10.1016/j.apsb.2016.04.004.
18. A. Srivastava, A. Pike, M. Swedrowska, S. Nash, and K. Grime, “In Vitro ADME Profiling of PROTACs: Successes, Challenges, and Lessons Learned from Analysis of Clinical PROTACs from a Diverse Physicochemical Space,” J. Med. Chem., vol. 68, no. 9, pp. 9584–9593, May 2025, doi: 10.1021/acs.jmedchem.5c00358.
19. C. K. Maurer et al., “In vitro and in vivo ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs©,” RSC Med. Chem., vol. 16, no. 4, pp. 1746–1757, Apr. 2025, doi: 10.1039/D4MD00854E.
20. M. Hanl et al., “Target Engagement Studies and Kinetic Live-Cell Degradation Assays Enable the Systematic Characterization of Histone Deacetylase 6 Degraders,” ACS Pharmacol. Transl. Sci., vol. 8, no. 9, pp. 3074–3089, Sep. 2025, doi: 10.1021/acsptsci.5c00247.
21. A. G. Waterson et al., “Identification of ligands for E3 ligases with restricted expression using fragment-based methods,” RSC Chemical Biology, 2025, doi: 10.1039/D5CB00198F.
22. C. A. Foley, F. Potjewyd, K. N. Lamb, L. I. James, and S. V. Frye, “Assessing the Cell Permeability of Bivalent Chemical Degraders Using the Chloroalkane Penetration Assay,” ACS Chem Biol, vol. 15, no. 1, pp. 290–295, Jan. 2020, doi: 10.1021/acschembio.9b00972.
23. A. K. Singh et al., “Targeted design, synthesis, molecular dynamics, ADME and in –vitro anticancer assessment of oxo-tetrahydro-pyrimidin-benzenesulfonamide hybrids as potential BRAFV600E inhibitors,” Sci Rep, vol. 15, no. 1, p. 35088, Oct. 2025, doi: 10.1038/s41598-025-18835-9.
24. K. Y. Wu, T. I. Hung, and C. A. Chang, “PROTAC-induced Protein Structural Dynamics in Targeted Protein Degradation,” eLife, vol. 13, Jan. 2025, doi: 10.7554/eLife.101127.2.
25. Y. Gharbi and R. Mercado, “A comprehensive review of emerging approaches in machine learning for de novo PROTAC design,” Digital Discovery, vol. 3, no. 11, pp. 2158–2176, Nov. 2024, doi: 10.1039/D4DD00177J.
26. P. Rossetti, G. Apprato, G. Caron, G. Ermondi, and M. Rossi Sebastiano, “DegraderTCM: A Computationally Sparing Approach for Predicting Ternary Degradation Complexes,” ACS Med Chem Lett, vol. 15, no. 1, pp. 45–53, Dec. 2023, doi: 10.1021/acsmedchemlett.3c00362.
27. D. P. Bondeson et al., “Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead,” Cell Chem Biol, vol. 25, no. 1, pp. 78-87.e5, Jan. 2018, doi: 10.1016/j.chembiol.2017.09.010.

About The Author

Nicole Alizade is a molecular biologist specializing in synthetic biology and structural biochemistry for protein engineering. Trained at Sorbonne University, her current research investigates programmable intracellular DNA synthesis applications through re-engineered nanopores for next-generation therapeutic platforms. Beyond the lab, she is engaged in translating academic innovation into biotech entrepreneurship, focusing on the interface between molecular design and practical application in drug discovery.