Heterobifunctional small molecule degraders are a subset of targeted protein degraders (TPDs), consisting of two ligands joined by a linker to induce proteasomal degradation of a target protein. As ...compared to traditional small molecules these compounds generally demonstrate inflated physicochemical properties, which may require innovative formulation strategies to enable their delivery and exert pharmacodynamic effect. The blood brain barrier (BBB) serves an essential function in human physiology, but its presence requires advanced approaches for treating central nervous system (CNS) diseases. By integrating emerging modalities like TPDs with conventional concepts of drug delivery, novel strategies to overcome the BBB can be developed. Amongst the available routes, lipid and polymer-based long-acting delivery seems to be the most amenable to TPDs, due to their ability to encapsulate lipophilic cargo and potential to be functionalized for targeted delivery. Another key consideration will be understanding E3 ligase expression in the different regions of the brain. Discovery of new brain or CNS disease specific E3 ligases could help overcome some of the barriers currently associated with CNS delivery of TPDs. This review discusses the current strategies that exist to overcome and improve therapeutic delivery of TPDs to the CNS.
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•Heterobifunctional small molecule Targeted Protein Degraders (TPD) have little in common with CNS penetrant molecules based on principal component analysis.•CNS delivery strategies for TPDs include physicochemical optimization, bypassing the BBB, passive transport, and targeting formulations.•Long-acting drug delivery technologies that are lipid or polymer based may be good choices for TPDs, complementing their mechanism of action.
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Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal ...chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.
Protein degraders are emerging as potent therapeutic tools to address neurological disorders and many complex diseases. It offered several key advantages, including the doses, drug resistance, and ...side effects over traditional occupancy-based inhibitors. Translation of chemical degraders into a clinical therapy for neurodegenerative disorders has a well-documented knowledge and resource gap. Researchers strive to develop clinical candidates employing chemical degraders' technologies, including hydrophobic tagging, molecular glues, proteolysis targeting chimeras (PROTACs), specific and nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent protein erasers (SNIPERs), autophagy targeted chimeras, and autophagosome-tethered compounds for targeted degradation of pathological markers in neurodegenerative disease. Herein, we examined the present state of chemical-mediated targeted protein degradation in the quest for medications to treat neurodegenerative diseases. We further identified targeted degraders under clinical development for neurodegenerative diseases summarizing pertinent discoveries guiding the future of degradation therapeutics. We also addressed the necessary pharmacological interventions needed to achieve unprecedented therapeutic efficacy and its associated challenges.
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•Protein degraders emerging tools for neurodegenerative disease therapy.•E3-independent degraders present distinct design and implementation problems.•VHL and CRBN are highly explored E3-ligase for PROTAC development.•Antibodies and molecular glue protein degraders are potent future CNS medicines.
Responsible for interpreting histone post-translational modifications, epigenetic reader proteins have emerged as novel therapeutic targets for a wide range of diseases. Chemical probes have been ...critical in enabling target validation studies and have led to translational advances in cancer and inflammation-related pathologies. Here, we present the most recently reported probes of reader proteins that recognize acylated and methylated lysine. We will discuss challenges associated with achieving potent antagonism of reader domains and review ongoing efforts to overcome these hurdles, focusing on targeting strategies including the use of peptidomimetic ligands, allosteric modulators, and protein degraders.
Targeted Protein degraders (TPDs) show promise in harnessing cellular machinery to eliminate disease-causing proteins, even those previously considered undruggable. Especially if protein turnover is ...low, targeted protein removal bestows lasting therapeutic effect over typical inhibition. The demonstrated safety and efficacy profile of clinical candidates has fueled the surge in the number of potential candidates across different therapeutic areas. As TPDs often do not comply with Lipinski's rule of five, developing novel TPDs and unlocking their full potential requires overcoming solubility, permeability and oral bioavailability challenges. Tailored in-vitro assays are key to precise profiling and optimization, propelling breakthroughs in targeted protein degradation.
The 17th EFMC Short Course on Medicinal Chemistry took place April 23–26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein ...Degradation (full title: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development). The course was oversubscribed, with 35 attendees and 6 instructors mainly from Europe but also from the US and South Africa, and representing both industry and academia. This report summarizes the successful event, key lectures given and topics discussed.
The 17th EFMC Short Course on Medicinal Chemistry this year focused on Small Molecule Protein Degraders, and the opportunities and challenges that they present as a novel modality of drug design and development. This conference report summarizes the successful event, the lectures delivered, and the topics discussed.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective ...therapeutic approach. We designed two small hybrid molecules (1 and 2) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin‐proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD.
Hunting down huntingtin: Two small hybrid molecules consisting of a ligand for ubiquitin ligase linked with a probe for protein aggregates induce the selective degradation of aggregates of the huntingtin protein (Htt) by the ubiquitin‐proteasome system. These compounds are effective in reducing Htt levels in fibroblasts derived from Huntington's patients, and could open up a promising new approach for the development of drugs against Huntington's disease.
Loss in potency is commonly observed in early drug discovery when moving from biochemical to more complex cellular systems. Among other factors, low permeability is often considered to cause such ...potency disconnects.
We developed a novel cellular disposition assay in MDCK cells to determine passive uptake clearance (PS
inf
), cell-to-medium ratios at steady-state (K
p
) and the time to reach 90% steady-state (TTSS
90
) from a single experiment in a high-throughput format.
The assay was validated using 40 marketed drugs, showing a wide distribution of PS
inf
and K
p
values. The parameters generally correlated with transcellular permeability and lipophilicity, while PS
inf
data revealed better resolution in the high and low permeability ranges compared to traditional permeability data. A linear relationship between the K
p
/PS
inf
ratio and TTSS
90
was mathematically derived and experimentally validated, demonstrating the dependency of TTSS
90
on the rate and extent of cellular accumulation.
Cellular disposition parameters could explain potency (IC
50
) disconnects noted for seven Bruton's tyrosine kinase degrader compounds in a cellular potency assay. In contrast to transcellular permeability, PS
inf
data enabled identification of the compounds with IC
50
disconnects based on their time to reach equilibrium. Overall, the novel assay offers the possibility to address potency disconnects in early drug discovery.
Protein degraders are currently under rapid development as a promising modality for drug discovery. They are compounds that orchestrate interactions between a target protein and an E3 ubiquitin ...ligase, prompting intracellular protein degradation through proteasomal pathway. More protein degraders identification will greatly promote the development of this field. BAG3 is widely recognized as an excellent therapeutic target in cancer treatments. Exploring protein degraders that target BAG3 degradation has profound implications. Herein, molecular docking was applied to assess binding energy between 81 clinical phase I kinase inhibitors and BAG3. BAG3 protein and mRNA level were detected by western blot and quantitative real-time PCR. CCK8 assay and colony formation assay were applied to detect the cell viability and proliferation rate. Cell death was accessed using flow cytometry combined with PI and Annexin V double staining. AZD7762, a Chk1 kinase inhibitor, was identified to induce BAG3 degradation in a ubiquitin-proteasome pathway. AZD7762-induced BAG3 degradation was not dependent on Chk1 expression or activity. CRBN, an E3 ligase, was identified to bind to BAG3 and mediated BAG3 ubiquitination in the presence of AZD7762. By targeting Chk1 and BAG3, two ideal therapeutic targets in cancer treatment, AZD7762 would be a powerful chemotherapy agent in the future.
