Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor α-Positive Breast Cancer DOI Creative Commons

Ying Feng,

Zhilin Zhang, Haowei Zhang

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(12), С. 3945 - 3954

Опубликована: Ноя. 14, 2024

Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% breast cases, whose predominant treatment is currently endocrine therapy. The main strategy therapy ERα+ to inhibit the ERα signaling pathway and downregulate levels, which often results in mutations ligand-binding domain (LBD) ERα, leading significant resistance subsequent patients. To combat drug resistance, we first proposed a novel aptamer PROTAC through specifically targeted degradation via targeting DNA-binding (DBD) ERα. We proved that this capable ubiquitination, inhibition proliferation cells tamoxifen-resistant cells. Furthermore, investigated mechanisms involved overcoming resistance. By circumventing associated LBD our approach provides promising avenue discovery new therapeutic agents.

Язык: Английский

TogoPhosTAC: A Ready-To-Go and Adaptable Targeted Protein Dephosphorylation System DOI Creative Commons
Po‐Han Chen,

Yu-Yu Chen,

Dong-Ting Ke

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Abstract Phosphorylation targeting chimeras (PhosTACs) recruit phosphatases to dephosphorylate target proteins by proximity-induced protein interactions. However, recruiting a phosphatase subunit or holoenzyme using small molecules without compromising its activity adversely disturbing cellular function remains challenging. In addition, many do not have favorable activator binder currently. To overcome these limitations, here, we report an adapted mode of action, named togoPhosTAC, based on the molecule PhosTAC, engineered fusion FKBP12(F36V)-phosphatase, and lipid-based delivery system for targeted dephosphorylation. Through nanoparticles, delivered pre-fused complex PhosTACs FKBP12(F36V)-phosphatases in mRNA format directly rapid efficient intracellular The togoPhosTAC was able epidermal growth factor receptor (EGFR), tau, α-synuclein. Furthermore, togoPhosTAC-mediated tau dephosphorylation also correlates with reduced aggregation. sum, our hybrid biologic adaptor strategy bypassed challenges ligand development provided alternative generalizable solution precise modulation in cellulo.

Язык: Английский

Процитировано

0
mRNA PROTACs: engineering PROTACs for high‐efficiency targeted protein degradation DOI
Xiaoqi Xue, Chen Zhang, Xiaolin Li

и другие.

MedComm, Год журнала: 2024, Номер 5(2)

Опубликована: Фев. 1, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) are essential bifunctional molecules that target proteins of interest (POIs) for degradation by cellular ubiquitination machinery. Despite significant progress made in understanding PROTACs' functions, their therapeutic potential remains largely untapped. As a result the success highly flexible, scalable, and low‐cost mRNA therapies, as well advantages first generation peptide PROTACs (p‐PROTACs), we present time an engineering (m‐PROTACs) strategy. This design combines von Hippel–Lindau (VHL) recruiting encoding POI‐binding to form m‐PROTAC promote POI degradation. We then performed proof‐of‐concept experiments using two m‐PROTACs targeting cancer‐related proteins, estrogen receptor alpha B‐cell lymphoma‐extra large protein. Our results demonstrated could successfully degrade POIs different cell lines more effectively inhibit proliferation than traditional p‐PROTACs. Moreover, vivo experiment led tumor regression 4T1 mouse xenograft model. finding highlights enormous promising approach targeted protein therapy.

Язык: Английский

Процитировано

3
Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor α-Positive Breast Cancer DOI Creative Commons

Ying Feng,

Zhilin Zhang, Haowei Zhang

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(12), С. 3945 - 3954

Опубликована: Ноя. 14, 2024

Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% breast cases, whose predominant treatment is currently endocrine therapy. The main strategy therapy ERα+ to inhibit the ERα signaling pathway and downregulate levels, which often results in mutations ligand-binding domain (LBD) ERα, leading significant resistance subsequent patients. To combat drug resistance, we first proposed a novel aptamer PROTAC through specifically targeted degradation via targeting DNA-binding (DBD) ERα. We proved that this capable ubiquitination, inhibition proliferation cells tamoxifen-resistant cells. Furthermore, investigated mechanisms involved overcoming resistance. By circumventing associated LBD our approach provides promising avenue discovery new therapeutic agents.

Язык: Английский

Процитировано

0