Chemistries of bifunctional PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

Language: Английский

---

Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(20), P. 15603 - 15671

Published: Sept. 29, 2022

Glycoconjugates are major constituents of mammalian cells that formed via covalent conjugation carbohydrates to other biomolecules like proteins and lipids often expressed on the cell surfaces. Among three classes glycoconjugates, proteoglycans glycoproteins contain glycans linked protein backbone amino acid residues such as Asn for N-linked Ser/Thr O-linked glycans. In glycolipids, a lipid component glycerol, polyisoprenyl pyrophosphate, fatty ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined biosynthetically understood, especially those associated with human diseases, accessible new drug, diagnostic, therapeutic developments. This review describes status advances in biological study applications natural synthetic including proteoglycans, glycoproteins, glycolipids. The scope, limitations, novel methodologies synthesis clinical development vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., their future prospectus discussed.

Language: Английский

---

Structure-based drug design with geometric deep learning

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 79, P. 102548 - 102548

Published: Feb. 25, 2023

Structure-based drug design uses three-dimensional geometric information of macromolecules, such as proteins or nucleic acids, to identify suitable ligands. Geometric deep learning, an emerging concept neural-network-based machine has been applied macromolecular structures. This review provides overview the recent applications learning in bioorganic and medicinal chemistry, highlighting its potential for structure-based discovery design. Emphasis is placed on molecular property prediction, ligand binding site pose de novo The current challenges opportunities are highlighted, a forecast future presented.

Language: Английский

---

Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 145(1), P. 385 - 391

Published: Dec. 21, 2022

Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in those so-called "undruggable" proteins. However, the potential systemic toxicity of PROTACs caused by undesired off-tissue may limit application clinical practice. Here we reported a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy to precisely and spatiotemporally control through X-ray radiation. We demonstrated this concept incorporating inducible phenyl azide-cage bromodomain (BRD)-targeting form first RT-PROTAC. The RT-PROTAC exhibits little activity but can be activated radiation vitro vivo. Activated degrades BRD4 BRD2 with comparable effect degrader synergistic antitumor potency radiotherapy MCF-7 xenograft model. Our work provides alternative vivo points avenue for reducing PROTACs.

Language: Английский

---

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(12), P. 8281 - 8287

Published: June 6, 2023

Heterobifunctional PROTAC degraders are gaining attention as a differentiated therapeutic modality with the potential for oral dosing in clinic. Belonging to beyond Rule of Five domain physicochemical property space, we have sought understand determinants absorption this class molecules rapid development novel agents. We collected large data set from that been dosed orally and intravenously rats estimate fraction absorbed dosing. Through estimation, effects differential hepatic clearance normalized, allowing better assessment absorption. demonstrate less permissive than mice. The properties then evaluated once compounds rank-ordered by absorbed. derive suggested design constraints on associated higher probability being

Language: Английский

---

Checkpoint Nano‐PROTACs for Activatable Cancer Photo‐Immunotherapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 35(6)

Published: Nov. 25, 2022

Abstract Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off‐target adverse effects. Herein, checkpoint nano‐proteolysis targeting chimeras (nano‐PROTACs) in combination with photodynamic tumor regression protein degradation block pathways for activatable cancer photo‐immunotherapy are reported. These nano‐PROTACs composed of a photosensitizer (protoporphyrin IX, PpIX) an Src homology 2 domain‐containing phosphatase (SHP2)‐targeting PROTAC peptide (aPRO) caspase 3‐cleavable segment. aPRO is activated by increased expression 3 cells after phototherapeutic treatment induces targeted SHP2 ubiquitin‐proteasome system. The persistent depletion blocks (CD47/SIRPα PD‐1/PD‐L1), thus reinvigorating antitumor macrophages T cells. Such strategy synergizes immunogenic phototherapy boost immune response. Thus, this study represents generalized platform modulate immune‐related improved anticancer therapy.

Language: Английский

---

Annual review of PROTAC degraders as anticancer agents in 2022

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116166 - 116166

Published: Jan. 25, 2024

Language: Английский

---

A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis‐Targeting Chimeras Enhanced Immunotherapy

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(12)

Published: Jan. 19, 2023

Although immunotherapy has revolutionized oncotherapy, only ≈15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) dysregulation polycomb ring finger oncogene BMI1 are potential reasons for failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA-PEG-PLGA) that loaded both imiquimod encapsulated CaCO3 nanoparticles (RC) cancer membrane (CCM)-coated mesoporous silica containing peptide-based proteolysis-targeting chimeras (PROTAC) paclitaxel (PepM@PacC). Upon injection, this undergoes in situ gelation, after which it degrades TME over time, releasing RC PepM@PacC respectively perform chemotherapy. Specifically, particles selectively manipulate tumor-associated macrophages dendritic cells activate T-cell immune response, while CCM-mediated homologous targeting endocytosis delivers into cells, where endogenous glutathione promotes disulfide bond cleavage release PROTAC peptide degradation frees particle pores elicit apoptosis meanwhile enhance immunotherapy. Thus, hydrogel, designed exploit multiple known vulnerabilities succeeds suppressing growth metastasis HNSCC.

Language: Английский

---

Ferroptosis Nanomedicine: Clinical Challenges and Opportunities for Modulating Tumor Metabolic and Immunological Landscape

ACS Nano, Journal Year: 2023, Volume and Issue: 17(16), P. 15328 - 15353

Published: Aug. 13, 2023

Ferroptosis, a type of regulated cell death driven by iron-dependent phospholipid peroxidation, has captured much attention in the field nanomedicine since it was coined 2012. Compared with other modes such as apoptosis and pyroptosis, ferroptosis many distinct features molecular mechanisms cellular morphology, representing promising strategy for treating cancers that are resistant to conventional therapeutic modalities. Moreover, recent insights collectively reveal is tightly connected maintenance tumor immune microenvironment (TIME), suggesting potential application therapies evoking robust antitumor immunity. From biochemical perspective, intricately multiple metabolic pathways, including iron metabolism, lipid redox etc., highlighting importance elucidate relationship between metabolism developing therapies. In this review, we provide comprehensive discussion on current understanding ferroptosis-inducing thoroughly discuss various traits tumors, which offer opportunities direct inhibition through nanointegrated approach. Extending from complex impact TIME, also discussed those important considerations development ferroptosis-based immunotherapy, challenges strategies enhance ferroptosis-enabled immunostimulatory effects while avoiding side effects. We envision study may facilitate translation nanomedicines treatment.

Language: Английский

---

Molecular Glue Discovery: Current and Future Approaches

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(14), P. 9278 - 9296

Published: July 12, 2023

The intracellular interactions of biomolecules can be maneuvered to redirect signaling, reprogram the cell cycle, or decrease infectivity using only a few dozen atoms. Such "molecular glues," which drive both novel and known between protein partners, represent an enticing therapeutic strategy. Here, we review methods approaches that have led identification small-molecule molecular glues. We first classify current FDA-approved glues facilitate selection discovery methods. then survey two broad method strategies, where highlight importance factors such as experimental conditions, software packages, genetic tools for success. hope this curation methodologies directed will inspire diverse research efforts targeting multitude human diseases.

Language: Английский

---